id000047 10.3205/id000047 urn:nbn:de:0183-id0000476 Leitlinie Guideline Calculated parenteral initial treatment of bacterial infections: Economic aspects of antibiotic treatment Wilke Wilke Michael M Dr.

inspiring-health Dr. Wilke GmbH, Waldmeisterstraße 72, 80935 München, Deutschlandinspiring-health Dr. Wilke GmbH, München, Deutschland

inspiring-health Dr. Wilke GmbH, Waldmeisterstraße 72, 80935 München, Germanyinspiring-health Dr. Wilke GmbH, Munich, Germany

michael.wilke@inspiring-health.de author Hübner Hübner Claudia C

Lehrstuhl für Allgemeine Betriebswirtschaftslehre und Gesundheitsmanagement, Universität Greifswald, DeutschlandLehrstuhl für Allgemeine Betriebswirtschaftslehre und Gesundheitsmanagement, Universität Greifswald, Deutschland

Lehrstuhl für Allgemeine Betriebswirtschaftslehre und Gesundheitsmanagement, Universität Greifswald, GermanyLehrstuhl für Allgemeine Betriebswirtschaftslehre und Gesundheitsmanagement, Universität Greifswald, Germany

author Kämmerer Kämmerer Wolfgang W

Klinische Pharmazie, Apotheke des Universitätsklinikums Augsburg, DeutschlandKlinische Pharmazie, Apotheke des Universitätsklinikums Augsburg, Deutschland

Klinische Pharmazie, Apotheke des Universitätsklinikums Augsburg, GermanyKlinische Pharmazie, Apotheke des Universitätsklinikums Augsburg, Germany

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 03 Dies ist das siebzehnte 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.Dieses Kapitel setzt sich mit den ökonomischen Effekten der antiinfektiven Therapie auseinander. Jede Behandlungsentscheidung ist auch eine kostenrelevante Entscheidung. Die Autoren beleuchten insbesondere die Frage, ob es Evidenz dafür gibt, das klinische wirksame Strategien auch ökonomisch günstig sind. Unter anderem werden Antibiotic Stewardship Programme (ABS), Leitlinienadhärenz in der Initialtherapie, De-Eskalation, Sequenztherapie sowie das therapeutische Drug Monitoring. Ökonomisch günstig sind sowohl direkte Kosteneinsparungen als auch die Verkürzung der Verweildauer um Ressourcen schneller wieder bereit zu stellen. This is the seventeenth 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.This chapter analyses economic aspects of antiinfective therapy. Any treatment decision is also a cost decision. In this chapter the authors particularly analyse whether or not there is evidence that certain clinically effective strategies as Antimicrobial Stewardship programs (AMS), guideline adherent initial therapy, early diagnostics, De-escalation, sequence therapy or therapeutic drug monitoring also have benficial economic effects. These can be direct savings or shortening of length of stay to free resources. EinführungDie kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen zielt darauf ab, dass zu einem möglichst frühen Zeitpunkt das richtige Antibiotikum gewählt wird, um die größtmögliche Chance auf Heilung der Infektion herbeizuführen. Darüber hinaus sollen die Empfehlungen zur kalkulierten Therapie auch einen Beitrag dazu leisten, dass die Entwicklung von Resistenzen minimiert wird. Im Folgenden sollen die ökonomischen Aspekte der Antibiotika-Therapie analysiert und Strategien vorgestellt werden, die aus ökonomischer Sicht günstig sind. Praktisch alle Studien und Publikationen zur ökonomischen Bewertung bestimmter Antibiotika-Therapiestrategien zeigen, dass klinische (Zeit bis Heilung, Überleben, Anteil Superinfektionen) und ökonomische Vorteile Hand in Hand gehen. Somit führt keine der hier vorgestellten, ökonomisch günstigen Therapiestrategien zu Nachteilen im klinischen Outcome. In den meisten europäischen Ländern, einschließlich den deutschsprachigen, sind im Krankenhaus Vergütungssysteme im Einsatz, die auf den so genannten „Diagnosis-Related Groups (DRG)“ basieren. Diese Systeme haben als Gemeinsamkeit, dass sie den Krankenhausaufenthalt ausgehend von der Hauptdiagnose, den durchgeführten Interventionen (Operationen und andere Prozeduren) und den eventuell vorhandenen Nebendiagnosen (z.B. nosokomiale Infektionen) pauschal vergüten. Gerade in diesen Vergütungssystemen sind alle diagnostischen und therapeutischen Strategien, die zu einer Verlängerung der Verweildauer führen, von vorneherein ökonomisch ungünstig, da die Vergütung in aller Regel auf den mittleren Kosten der Patienten in einer Fallpauschale basiert, die wiederum stark von der mittleren Verweildauer beeinflusst sind. Verlängert sich der stationäre Aufenthalt über die mittlere Verweildauer hinaus, so kostet die Behandlung in aller Regel mehr als die Vergütung des Falles erbringt. In der klassischen Pharmakoökonomie stehen häufig Betrachtungen von Arzneimittelkosten im Vordergrund. Nachdem diese Kosten im Allgemeinen nur ca. 4% der Kosten (Intensivstationen 10%) im Krankenhaus ausmachen, treten sie hinter die Kosten, die mit einer längeren Verweildauer verbunden sind, zurück. Dennoch sollen auch Strategien betrachtet werden, die durch gezielte Intervention zu einer Reduktion der Arzneimittelkosten führen. Schließlich haben die Autoren eine einfache Anleitung in diesen Text aufgenommen, mit der eigene Analysen durchgeführt werden können.Nicht betrachtet werden hier pharmakoökonomische Kenngrößen wie Kosteneffektivität oder Kosten pro gewonnenem, qualitätsadjustierten Lebensjahr (Cost/QALY), da diese Betrachtungen im deutschsprachigen Raum keine große Rolle spielen und lediglich in einigen angelsächsischen Ländern zur Entscheidungsfindung herangezogen werden, ob bestimmte Arzneimittel vergütet werden sollen oder nicht.Ziel dieses Textes ist es, dem Leser eine schnelle Übersicht ökonomisch empfehlenswerter Strategien in Form einer Tabelle zu geben, die neben den Strategien auch einen Empfehlungsgrad enthält, damit entschieden werden kann, welche Strategien systematisch zur Anwendung kommen sollen (siehe Tabelle 1 ). IntroductionCalculated parenteral initial treatment of bacterial diseases in adults aims at choosing the right antibiotic at the earliest possible moment in order to maximize the chances of curing the infection. In addition, the recommendations for calculated treatment should also contribute to minimizing risk of developing resistance. In the following, the economic aspects of antibiotic treatment will be analyzed and strategies presented that are favorable from an economic point of view. Practically all studies and publications on the economic evaluation of certain antibiotic treatment strategies show that clinical (time to cure, survival, proportion of superinfections) and economic benefits go hand in hand. Thus, none of the economically favorable treatment strategies presented here have a negative impact on the clinical outcome. In most European countries, including the German-speaking countries, remuneration systems based on the so-called “diagnosis-related groups (DRG)” are in use in hospitals. These systems have in common that they reimburse for a hospital stay on the basis of the principal diagnosis, interventions performed (surgeries and other procedures) and any secondary diagnoses (for example nosocomial infections). In these compensation systems in particular, all diagnostic and therapeutic strategies that lead to a longer hospital stay from the outset are economically unfavorable, since reimbursement usually takes the form of a per-case lump sum based on the average cost of a patient, which in turn is strongly influenced by the average length of stay. If the in-patient stay extends beyond the average length of stay, treatment usually costs more than the reimbursement for the case. In classical pharmacoeconomics, considerations of drug costs are often in the foreground. Since these costs generally only account for about 4% of the costs in a hospital (intensive care wards 10%), they are well below the costs associated with longer stays. Nevertheless, strategies should also be considered that lead to a reduction in the cost of medicines through targeted intervention. Finally, the authors have included a simple guide in this text that readers can use to perform their own analyzes.Pharmacoeconomic parameters such as cost-effectiveness or costs per quality-adjusted year of age (Cost/QALY) are not considered, since these considerations do not play a major role in German-speaking countries and are only used in some English-speaking countries to decide whether or not certain medicines should be reimbursed.The aim of this text is to give readers a quick overview of economically advisable strategies in the form of a table, which in addition to the strategies also contains a level of recommendation in order to decide which of them should be used systematically (see Table 1 ). Diagnostische und therapeutische Strategien im EinzelnenAdäquate InitialtherapieDie Auswahl des Antibiotikums zu Beginn der Therapie – gerade bei kritisch kranken Patienten – entscheidet zu einem hohen Maße über das klinische und ökonomische Outcome. Eine inadäquate Therapie ist mit erheblich höherer Sterblichkeit , , , , und meist auch höheren Kosten verbunden , , , , . Der Begriff „inadäquate Therapie“ ist jedoch sehr allgemein. Im Folgenden werden Aspekte vorgestellt, die einzeln oder zusammengenommen zu inadäquater Initialtherapie führen, und Beispiele aus der Literatur aufgezeigt.Einhaltung von LeitlinienIn Leitlinien und Empfehlungen werden diagnostische und therapeutische Strategien zusammengeführt, die sicherstellen sollen, dass bei bestimmten Infektionen die häufigsten Erreger – unter Berücksichtigung der aktuellen Resistenzsituation – mit der Initialtherapie erfasst werden. Somit stellt die Einhaltung von Leitlinien, einschließlich lokaler Empfehlungen auf der Basis nationaler und internationaler Leitlinien, einen wichtigen Einflussfaktor auf klinische und ökonomische Ergebnisse der Therapie dar. In der Literatur existieren Beispiele für prospektiv randomisierte Studien , , , Fallkontrollstudien und so genannte „interrupted time series“ Analysen, vulgo „vorher/nachher“ , , , . Für die Einhaltung von Leitlinien sprechen die Autoren nach Sichtung der Literatur und Einschätzung der Evidenz eine starke Empfehlung aus (A).Berücksichtigung der lokalen Resistenzlage und des patienten-individuellen Risikos für das Vorliegen resistenter ErregerEine inadäquate Antibiotika-Therapie ist mit erhöhter Letalität und verlängerten Krankenhausverweilzeiten assoziiert , , . Daher ist es nicht nur aus klinischer sondern auch aus wirtschaftlicher Sicht relevant, dass eine adäquate Antibiotika-Therapie so früh wie möglich erfolgt, idealerweise bereits mit der kalkulierten Initialtherapie.Viele Studien, die adäquate und nicht-adäquate Therapie miteinander vergleichen, stellen darüber hinaus fest, dass insbesondere Patienten, bei denen multiresistente Erreger als Infektionsursache nachgewiesen werden, häufig keine adäquate Initialtherapie erhalten haben , , , , , , , , .Die Resistenzrate, d.h. der Anteil der Stämme einer Bakterienspezies, der gegen eine oder mehrere antimikrobielle Substanzen resistent ist, ist als ein Faktor identifiziert worden, der die Kosteneffektivität von Antibiotika mit beeinflusst . Die Auswirkungen wurden in verschiedenen entscheidungsanalytischen Studien am Beispiel der ambulant erworbenen Pneumonie (CAP) untersucht , , . In Sensitivitätsanalysen konnte gezeigt werden, dass durch die Berücksichtigung der Resistenzraten von Streptococcus pneumoniae und Haemophilus influenzae bei der Wirkstoffauswahl das Versagen der First-Line-Therapie reduziert und somit eine Second-Line-Therapie nicht notwendig wurde, weniger Krankenhauseinweisungen erforderlich waren und die Letalität sank.Bei der Behandlung einer lebensbedrohlichen bakteriellen Infektion, bei der eine kalkulierte Antibiotika-Therapie initial zum Einsatz kommt, sind die Kenntnisse des lokalen, häufig sogar stationsspezifischen Erregerspektrums und der damit verbundenen Resistenzlage entscheidend. Hierfür ist es notwendig, dass die Resistenzstatistiken kontinuierlich durch den Mikrobiologen (oder Krankenhaushygieniker) erstellt, bewertet und den Klinikern kommuniziert werden. Eine besondere Rolle kommt dabei der mikrobiologischen Diagnostik zu. Sie hat zwei wichtige Funktionen zu erfüllen:Modifizierung einer initial kalkulierten Antibiotika-Therapie durch den mikrobiologischen Befund und Schaffen einer Datengrundlage zur Bestimmung des lokalen Erreger- und Resistenzspektrums, auf das zukünftige kalkulierte Antibiotikastrategien ausgerichtet werden.Gerade für den ersten Punkt ist es wichtig, möglichst rasch ein mikrobiologisches Ergebnis zu erhalten. Hier lässt sich der Einsatz schneller, kostenintensiver Diagnostikverfahren durchaus wirtschaftlich rechtfertigen , . Ziel ist es, durch die schnelle Bestimmung des Resistenzstatus eine frühzeitige De- bzw. Eskalation der kalkulierten Initialtherapie einzuleiten und damit die Dauer einer möglichen inadäquaten Therapie mit ihren negativen Folgen zu reduzieren. Eine Kosteneffizienz konnte in ökonomischen Modellrechnungen, z.B. für die PCR-gesteuerte kalkulierte Antibiotika-Therapie, belegt werden , .Darüber hinaus ist es wichtig, patienteneigene Risikofaktoren, die auf eine Infektion mit einem multiresistenten Erreger hindeuten, bei der Therapieauswahl mit zu berücksichtigen. Hierzu zählen vorrangig eine bereits vorangegangene Antibiotika-Therapie, die Kolonisation oder Infektion mit einem MRE oder Erreger mit besonderer Resistenz in der Anamnese, eine Infektion, die im Krankenhaus erworben wurde oder ein vorausgegangener Krankenhausaufenthalt, chronische Immunsuppression (Krebs, COPD, Diabetes, MTX-Therapie bei PCP, u.a.) sowie Aufenthalt auf einer Intensivstation (ggf. mit Beatmung) und akutes oder chronisches Nierenversagen, um nur die wichtigsten zu nennen , , , , , . Die Bewertung/Gewichtung von derartigen Risikofaktoren wird u.a. bei der Auswahl geeigneter Antibiotika im Rahmen der kalkulierten Initialtherapie von Pneumonien empfohlen , , .Die Nicht-Berücksichtigung des Risikos führt zu schlechteren klinischen Ergebnissen und höheren Therapiekosten. Bei diesen Patienten kann die Wahl eines Antibiotikums, das multiresistente Erreger in der Initialtherapie mit erfasst, die in klinischer und ökonomischer Hinsicht bessere Wahl darstellen. Sobald der Erreger bekannt ist, sollte die Therapie im Sinne einer De-Eskalation entsprechend angepasst werden. Der Nutzen einer frühzeitigen Berücksichtigung von multiresistenten Erregern bei entsprechenden Risikopatienten wurde bisher ausschließlich in retrospektiven Fallkontrollstudien gezeigt, trotzdem geben die Autoren eine starke Empfehlung (A) für diese Strategie ab.Schnelle Diagnostik mit modernen VerfahrenGerade weil die Fehleinschätzung des Risikos hinsichtlich des Vorliegens eines Problemerregers häufig zu einer inadäquaten Initialtherapie führt und die Erregeridentifizierung mittels Kultur in der klinischen Praxis 48 h oder länger dauert, stellt sich die Frage, ob neuere diagnostische Verfahren wie Realtime PCR, MALDI-TOF oder die PCR-basierte Elektronenspray Massenspektroskopie (PCR/ESI-MS) einen Beitrag zur adäquaten Initialtherapie leisten und Kosten senken. Da diese Verfahren im Vergleich zur herkömmlichen Diagnostik sehr teuer sind, stellt sich die Frage, wann sie nützlich sind. Verschiedene Autoren haben hierzu Untersuchungen durchgeführt und dabei unterschiedliche wissenschaftliche Ansätze gewählt (Experteneinschätzung auf der Basis von Testergebnissen , , Modellierung , Vorher/nachher , , . Eine Arbeit hat gezeigt, dass die schnelle Testung den Verbrauch von Vancomycin senken und die Verweildauer verkürzen konnte . Nach Einschätzung der Evidenz für die vorliegenden Arbeiten, die sich explizit mit den ökonomischen Effekten schneller Diagnostik befassen, geben die Autoren eine mittlere Empfehlung für diese Strategie ab (B).Antibiotic Stewardship Programme (ABS)Viele Maßnahmen zur Optimierung der Antibiotika-Therapie lassen sich unter dem Begriff ABS subsummieren. Hier wurde analysiert, welche Evidenz es gibt, dass umfangreiche Programme mit Maßnahmen wieErstellung von hauseigenen EmpfehlungenRegelmäßige Verordnungsanalysen mit Visiten und kontinuierlichem FeedbackBeratung durch ABS-Experten (z.B. Infektiologen oder klinische Pharmazeuten)Restriktion bestimmter Antibiotika-Klassenklinisch und ökonomisch sinnvoll sind. Eine Reihe internationaler Autoren unterstreichen dies deutlich , , . Im Jahr 2013 erschienen ein Cochrane Review sowie eine S3-Leitlinie zu dieser Thematik . Insgesamt liegt für die Einführung von ABS-Programmen und deren klinischem wie ökonomischen Nutzen nach Ansicht der Autoren eine sehr gute Evidenz vor und sie sprechen eine starke Empfehlung (A) aus.SequenztherapieEine parenteral-orale Folgebehandlung (Sequenztherapie) bietet die Möglichkeit, die in einer Klinik parenteral begonnene Antibiotika-Therapie (ambulant) oral fortzusetzen. Dadurch wird die Dauer der intravenösen Therapie reduziert, ohne negative Auswirkungen auf den Therapieerfolg zu haben . Neben der Senkung der infusionsbedingten Infektionsrisiken und einer schnelleren Mobilisierung des Patienten gibt es eine Vielzahl von ökonomischen Vorteilen, die für eine Sequenztherapie sprechen.Durch eine frühzeitige Umstellung auf orale Arzneiformen wird eine signifikante Verkürzung der Krankenhausverweildauer erreicht, was in DRG-pauschalisierten Entgeltsystemen der Krankenhausfinanzierung eine erhebliche Rolle spielen kann. So konnten beispielsweise das Team um Nathwani und Eckmann in einer europaweiten retrospektiven Analyse der Therapie von MRSA-assoziierten Haut- und Weichgewebeinfektionen durch die Einführung der Sequenztherapie eine Verkürzung der Krankenhausverweildauer im Mittel um 6,2 Tage und ein daraus resultierendes Einsparpotential von 2.000 Euro pro Patient belegen . Zu ähnlichen Ergebnissen kamen Gray et al. mit ihrer Studie in 5 Krankenhäusern in Großbritannien, in der sie Einsparungen in Höhe von 363 Britischen Pfund pro Patient ermittelten .Als weitere Gründe für die ökonomische Überlegenheit der Sequenztherapie gegenüber der durchgängigen parenteralen Therapie lassen sich geringere Antibiotikakosten sowie geringere Personalkosten für die Zubereitung und Applikation der parenteralen Antibiotika anführen. Die Effekte zeigen sich dabei nicht nur für den klinischen Bereich, sondern auch in der prä- und poststationären Versorgung.Auch wenn für die Sequenztherapie und deren ökonomische Vorteile vorwiegend retrospektive Untersuchungen vorliegen, sprechen die Autoren – aus ökonomischer Sicht – eine starke Empfehlung (A) aus.De-EskalationNeben der Sequenztherapie kann auch die Deeskalation einen Beitrag zur Optimierung der klinisch-ökonomischen Balance liefern. Ziel ist es, eine kalkulierte initiale Breitspektrum-Antibiotika-Therapie durch eine gezieltere, d.h. gleich wirksame aber mit schmalerem Spektrum versehene Substanz zu ersetzen. Voraussetzungen sind hierfür:Vorliegen spezifischer und plausibler mikrobiologischer Befunde Klinische Besserung (Patient hat gut auf die initiale Therapie angesprochen)Durch die Reduktion der Therapiebreite und damit der Antibiotikalast soll die Resistenzentwicklung durch eine Minimierung des Selektionsdruckes günstig beeinflusst werden. Die Patientensicherheit wird verbessert durch das Auftreten von weniger unerwünschten Arzneimittelwirkungen und Superinfektionen . Aus ökonomischer Sicht ergeben sich hierdurch teilweise erhebliche Einsparungen bei den Arzneimittelausgaben, nicht zuletzt auch durch die Reduktion der Therapiedauer .Wie bei der Sequenztherapie, sind die Publikationen zum ökonomischen Effekt der De-Eskalation vorwiegend entweder retrospektive Analysen oder sekundäre Auswertungen von klinischen Studien. Die Autoren sprechen dennoch auch hier wieder eine starke Empfehlung (A) aus.Therapeutisches Drug Monitoring (TDM)Gerade bei Antibiotika mit geringer therapeutischer Breite wie Vancomycin, aber auch bei Ansätzen zur prolongierten Therapie mit Beta-Lactam-Antibiotika ist die Spiegelbestimmung von Bedeutung. Für TDM bei Vancomycin konnte mehrfach gezeigt werden, dass die Reduktion nephrotoxischer Komplikationen mit TDM deutlich ist und somit – trotz der Kosten – zu erheblichen Einsparungen durch vermiedene Komplikationen führt , .Eine Analyse von 200 Intensivpatienten mit schweren Infektionen hat verschiedene Therapiestrategien mit Piperacillin/Tazobactam untersucht. Mit durchschnittlichen Gesamtkosten von 90,64 € für eine 7-tägige Behandlung mit Piperacillin/Tazobactam lag die kontinuierliche Applikation einer individuellen Dosis trotz zusätzlicher Kosten für das therapeutische Drug-Monitoring (TDM, 26,68 €) unter den Kosten der intermittierenden Bolusgabe entlang der Empfehlungen der Fachinformation von 3x 4,5 g (komplizierte Harnwegsinfektion, intraabdominelle Infektionen, Haut- und Weichteilinfektionen, 112,11 €) bzw. 4x 4,5 g (schwere Pneumonie, neutropene Erwachsene mit Fieber, wenn der Verdacht auf eine bakterielle Infektion besteht, 148,49 €). Zu diesem Ergebnis trugen einerseits reduzierte Arzneimittelkosten – 36,75 € [3x 4,5 g]/49,00 € [4x 4,5 g] Bolusapplikation versus 24,50 € [8 g (2–16 g), Median (Min, Max.)] kontinuierliche Applikation mit TDM – um ca. 30–50% und andererseits die geringeren Prozesskosten (Einmalartikel und Arbeitszeit für die Zubereitung und kontinuierliche Applikation (46,11€/61,48 &#8364;</PlainText></TextGroup> Bolusapplikation versus 24,42 &#8364; kontinuierliche Applikation) bei <TextLink reference="59"></TextLink>.</Pgraph><Pgraph>Obwohl eine der Studien zu Vancomycin eine randomisierte klinische Studie war, insgesamt aber vergleichsweise wenige Studien zu den &#246;konomischen Aspekten des TDM vorliegen, sprechen die Autoren eine Empfehlung vom Grad B aus.</Pgraph><SubHeadline>Bedeutung der Prozesskosten</SubHeadline><Pgraph>Sp&#228;testens mit Einf&#252;hrung der DRG wurden f&#252;r die Krankenh&#228;user die Analyse ihrer Prozesskosten und die hieraus resultierende Prozessoptimierung zwingend erforderlich. Hierbei gilt es, den Prozess der Arzneimitteltherapie von der Beschaffung des Arzneimittels bis zur Anwendung am Patienten zu ber&#252;cksichtigen.</Pgraph><Pgraph>Ein wichtiges Instrument zur Prozessoptimierung stellt dabei die Etablierung klinischer Behandlungspfade bzw. die Erstellung von Standard Operating Procedures (SOP) dar. Mit Hilfe dieser Behandlungspfade&#47;Prozessbeschreibung gelingt es, Kosten und Qualit&#228;t der Behandlung zu beschreiben und sicherzustellen. Als Teil der Behandlungspfade sind Standards in der Arzneimitteltherapie anzusehen. Antiinfektiva sind wegen ihrer hohen Bedeutung im Bereich der Kosten, aber auch ihrer hohen Bedeutung f&#252;r die Qualit&#228;t und den Erfolg der Behandlung, eine wichtige Arzneistoffgruppe. Diese Therapiestandards sind gleichfalls auch ein wichtiger Bestandteil von ABS-Programmen. </Pgraph><Pgraph>Ein bedeutsames Kriterium f&#252;r die Auswahl der in die Behandlungspfade&#47;Prozesse passenden Antiinfektiva wird dabei der betriebswirtschaftlich-pharmako&#246;konomischen Analyse der Therapiealternativen aus der Perspektive eines Krankenhauses zukommen. Hierbei sind neben den Einkaufspreisen der Arzneimittel auch andere Verbr&#228;uche von Ressourcen zu ber&#252;cksichtigen.</Pgraph><Pgraph>Auch sollte hinterfragt werden, inwieweit das eingesetzte Antiinfektivum Aspekten des Qualit&#228;tsmanagements, der Qualit&#228;tssicherung, des Prozessmanagements, der Patientenorientierung und Mitarbeiterorientierung gen&#252;gt. In eine solche Analyse gehen daher folgende Parameter ein:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Personalaufwand pro Applikation: Unter DRG-Bedingungen (erh&#246;hte Leistungsdichte, reduzierter Personalbestand) ist eine Reduktion der Applikationsh&#228;ufigkeit als positiv zu werten. Auch die pro Applikation entstehenden Personalkosten sind ein wichtiges Kriterium: sie werden in der Literatur mit 2&#8211;4 &#8364; bzw. US&#36; pro Applikation angegeben <TextLink reference="60"></TextLink>, <TextLink reference="61"></TextLink>;</ListItem><ListItem level="1">die Kosten der zugeh&#246;rigen Applikationshilfsmittel wie Spritze, Kan&#252;len, Infusionsbesteck etc. In der Literatur werden diese Kosten je nach Applikationsart mit <TextGroup><PlainText>1&#8211;4 &#8364;</PlainText></TextGroup> angegeben <TextLink reference="61"></TextLink>;</ListItem><ListItem level="1">eine geringere Fehlerrate: In Untersuchungen und den hieraus resultierenden Empfehlungen aus angels&#228;chsischen L&#228;ndern konnte gezeigt werden, dass die Zahl der Anwendungsfehler von Arzneimitteln mit der Reduzierung der Applikationsh&#228;ufigkeit und der Einfachheit der Zubereitung abnimmt <TextLink reference="62"></TextLink>. Dabei ist auch die erforderliche Anzahl der Zubereitungsschritte zu ber&#252;cksichtigen. So sollten, wenn immer m&#246;glich, Fertigpr&#228;parate eingesetzt werden;</ListItem><ListItem level="1">die m&#246;gliche Verwechslungsgefahr; </ListItem><ListItem level="1">die Kosten f&#252;r ein erforderliches Monitoring, aber auch die mittels Monitoring erreichbare Senkung des Antiinfektivaverbrauchs.</ListItem></UnorderedList></Pgraph><Pgraph>Ziel dieser Prozess- und Prozesskostenbetrachtung ist die Verbesserung der Qualit&#228;t bei gleichzeitiger Kostenoptimierung. Kostenoptimierung in diesem Sinn bedeutet, dass mit Hilfe der beschriebenen Analyse dasjenige Antiinfektivum unter gleich guten Wirkstoffen zum Einsatz kommt, dass den geringsten Ressourcenverbrauch aufweist. Aufgrund der geringen Zahl von Studien, die sich explizit mit dem Thema Prozesskosten sowie Fehlerkosten bei der Anitbiotikatherapie befassen, sprechen die Autoren eine Empfehlung Grad B aus.</Pgraph><SubHeadline>&#214;konomische Konsequenzen bei steigender Resistenzh&#228;ufigkeit</SubHeadline><Pgraph>Aus klinischer wie &#246;kologischer Sicht sollte das Risiko der Selektion von Antibiotika-resistenten Mikroorganismen minimiert werden, da Infektionen, die durch multiresistente oder gar panresistente Bakterien verursacht werden, mit einem (z.T. erheblich) erh&#246;hten Letalit&#228;tsrisiko f&#252;r die Patienten einhergehen. Eine Reihe von Ver&#246;ffentlichungen &#252;ber die Bedrohung der Gesundheit durch Antibiotika-resistente Erreger hat sich auch den damit vebundenen Kosten gewidmet. In den USA werden laut &#8222;State of the World&#8217;s Antibiotics&#8220; Bericht Kosten von US&#36; 20 Milliarden im Gesundheitswesen sowie Produktivit&#228;tsverluste von weiteren US&#36; 35 Milliarden genannt, welche durch 23.000 an Infektionen mit resistenten Erregern verstorbene Patienten verursacht werden <TextLink reference="63"></TextLink>. Der WHO Global Report 2014 zur Surveillance der Antibiotika-Resistenzen beinhaltet u.a. eine systematische Literaturanalyse zu den Kosten von Infektionen mit resistenten Mikroorganismen. Der sehr differenzierte Bericht kommt zu dem Schluss, dass die Zunahme resistenter Keime zu erh&#246;hten Kosten gef&#252;hrt hat, auf der bestehenden Datengrundlage jedoch keine globale Hochrechnung vorgenommen werden kann <TextLink reference="64"></TextLink>. Insbesondere wird darauf hingewiesen, dass die attributierbaren Mehrkosten von Infektionen durch resistente St&#228;mme im Vergleich zu Infektionen durch sensible St&#228;mme einer Erregerspezies in derselben Infektionsentit&#228;t &#246;konomisch betrachtet werden sollen. So liegen z.B. mehrere Arbeiten vor, die MRSA und MSSA Infektionen &#246;konomisch untersucht haben. Hier werden attributierbare Mehrkosten in H&#246;he von 8.000 &#8364; bis 17.000 &#8364; bzw. 13.900 US&#36; gesehen <TextLink reference="65"></TextLink>, <TextLink reference="66"></TextLink>, <TextLink reference="67"></TextLink>, <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink>. Anhand dieser Geldbetr&#228;ge ist leicht nachvollziehbar, wie die hohen Kosten der oben genannten Hochrechnung zustande gekommen sind. Sie erscheinen durchaus realistisch. Ein weiterer Bericht kommt zu der Aussage, dass die Zahl der Todesf&#228;lle durch Infektionen mit resistenten Erregern von heute weltweit 700.000 im Jahr 2050 bei 10 Millionen liegen wird, wenn keine weiteren Ma&#223;nahmen unternommen werden. Dies w&#252;rde bis 2050 in Summe zu einem &#8211; weltweiten &#8211; volkswirtschaftlichen Gesamtschaden von 100 Billionen US&#36; (100.000 Milliarden, im Original &#8222;100 Trillions&#8220; &#8211; US-Notation) f&#252;hren <TextLink reference="70"></TextLink>. Immerhin erkennen die Autoren an, dass erste Schritte zur Bew&#228;ltigung dieser globalen Krise bereits unternommen wurden. Intensivierte Forschung, durch die WHO koordinierte Aktionen in <TextGroup><PlainText>194 L</PlainText></TextGroup>&#228;ndern sowie Fortschritte im Verst&#228;ndnis der Genetik der Bakterien und schlie&#223;lich die Verbesserungen infektionspr&#228;ventiver Ma&#223;nahmen in Schwellenl&#228;ndern seien &#8222;Lichtblicke&#8220;.</Pgraph><Pgraph>Zusammenfassend kann festgehalten werden, dass Resistenzen gegen Antibiotika einen erheblichen direkten finanziellen und noch gr&#246;&#223;eren volkswirtschaftlichen Schaden verursachen. Gerade deshalb sollte dieses Thema auch zuk&#252;nftig mit auf der Agenda stehen, wenn &#252;ber die &#246;konomischen Aspekte der Antibiotika-Therapie gesprochen wird.</Pgraph><SubHeadline>Weiterf&#252;hrende Informationsquellen und deren Bewertung</SubHeadline><Pgraph>In Medline finden sich vermehrt auch Hinweise auf gesundheits&#246;konomische Arbeiten. Zu den Zeitschriften, die schwerpunktm&#228;&#223;ig Artikel zu gesundheits&#246;konomischen Fragestellungen ver&#246;ffentlichen, z&#228;hlen das von der Deutschen Fachgesellschaft f&#252;r Gesundheits&#246;konomie herausgegebene Journal &#8222;Gesundheits&#246;konomie und Qualit&#228;tsmanagement&#8220; sowie die internationalen, englischsprachigen Fachjournale wie &#8222;Health Economics&#8220;, &#8222;European Journal of Health Economics&#8220; und &#8222;Value in Health&#8220;.</Pgraph><Pgraph>Ein bekanntes Problem ist, dass nicht nur die zulassungsrelevanten Therapiestudien, sondern auch viele pharmako&#246;konomische Studien in Kooperation mit der Pharmaindustrie durchgef&#252;hrt werden. Derartige Studien pr&#228;sentieren in der Regel positive Ergebnisse f&#252;r meist hochpreisige Arzneimittelinnovationen und werden vielfach als Marketinginstrumente bei Au&#223;envertreterbesuchen oder auf Fachkongressen eingesetzt. Auf der anderen Seite erfolgt die Wahl der Analysenmethode oft ergebnisorientiert oder es werden umfangreiche und intransparente Modellrechnungen angewendet. F&#252;r den Nicht-&#214;konomen ist es schwierig, diesen Publikationsbias zu erkennen und den Stellenwert solcher Studien einzuordnen. Eine M&#246;glichkeit ist, sich bei der Recherche besonders auf Berichte von Health Technology Assessment (HTA) Agenturen wie dem National Institute for Health and Clinical Excellence (<Hyperlink href="http:&#47;&#47;www.evidence.nhs.uk&#47;">http:&#47;&#47;www.evidence.nhs.uk&#47;</Hyperlink>), dem Institut f&#252;r Qualit&#228;t und Wirtschaftlichkeit im Gesundheitswesen (<Hyperlink href="https:&#47;&#47;www.iqwig.de&#47;">https:&#47;&#47;www.iqwig.de&#47;</Hyperlink>) oder der Canadian Agency for Drugs and Technologies in Health (<Hyperlink href="http:&#47;&#47;www.cadth.ca&#47;">http:&#47;&#47;www.cadth.ca&#47;</Hyperlink>) zur&#252;ckzugreifen. Neben einer systematischen Darstellung und qualitativen Bewertung der verf&#252;gbaren Evidenz enthalten diese auch Bewertungen der Wirtschaftlichkeit von Arzneimitteln und anderen medizinischen Technologien. Diese beruhen teils auf vorhandenen, teils auf der Grundlage von eigenen &#246;konomischen Studien. Die zunehmende Vernetzung internationaler HTA-Agenturen und eine fortschreitende Standardisierung der Bewertungsmethoden &#252;ben einen zus&#228;tzlichen beg&#252;nstigenden Einfluss aus.</Pgraph><Pgraph>Sehr ausf&#252;hrlich werden Studien, aber auch HTA-Berichte, in der Datenbank des NHS Centre for Review and Dissemination (<Hyperlink href="http:&#47;&#47;www.crd.york.ac.uk&#47;crdweb&#47;">http:&#47;&#47;www.crd.york.ac.uk&#47;crdweb&#47;</Hyperlink>) dargestellt. Die NHS Economic Evaluation Database enth&#228;lt Studien, die in Current Contents, Clinical Medicine, Medline und CINAHL aufgef&#252;hrt werden sowie bei der Handsuche recherchiert werden k&#246;nnen. Anhand eines etwa 30 Kriterien umfassenden Schemas werden Studienziel, Design des klinischen und &#246;konomischen Studienteils sowie klinische und &#246;konomische Ergebnisse &#252;bersichtlich und detailliert pr&#228;sentiert. Zudem erfolgt eine knappe Bewertung der Studienqualit&#228;t.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Diagnostic and therapeutic strategies in detail"> <MainHeadline>Diagnostic and therapeutic strategies in detail</MainHeadline><SubHeadline>Adequate initial therapy</SubHeadline><Pgraph>The selection of the antibiotic at the beginning of treatment &#8211; especially in critically ill patients &#8211; determines the clinical and economic outcome to a high degree. Inadequate treatment is associated with significantly higher mortality <TextLink reference="1"></TextLink>, <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>, <TextLink reference="5"></TextLink> and usually higher costs <TextLink reference="1"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="7"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>. However, the term &#8220;inadequate treatment&#8221; is rather vague. In the following we present aspects, including examples from the literature, which individually or in combination lead to inadequate initial therapy.</Pgraph><SubHeadline>Compliance with guidelines</SubHeadline><Pgraph>Guidelines and recommendations combine diagnostic and therapeutic strategies designed to ensure that the most common pathogens in certain infections &#8211; factoring in the current resistance situation &#8211; are included in initial treatment. Thus, adherence to guidelines, including local recommendations based on national and international guidelines, is an important driver of clinical and economic outcomes of treatment. There are examples in the literature of prospective randomized studies <TextLink reference="10"></TextLink>, <TextLink reference="11"></TextLink>, <TextLink reference="12"></TextLink>, case-control studies and so-called &#8220;interrupted time series&#8221; analyzes &#8211; more commonly known as &#8220;before and after&#8221; <TextLink reference="13"></TextLink>, <TextLink reference="14"></TextLink>, <TextLink reference="15"></TextLink>, <TextLink reference="16"></TextLink>. After reviewing the literature and assessing the evidence, the authors strongly recommend (A) adherence to guidelines.</Pgraph><SubHeadline>Consideration of the local resistance situation and patient-specific risk regarding the presence of resistant pathogens</SubHeadline><Pgraph>Inadequate antibiotic treatment is associated with increased mortality and prolonged hospital stays <TextLink reference="2"></TextLink>, <TextLink reference="9"></TextLink>, <TextLink reference="17"></TextLink>. Therefore, it is relevant not only from a clinical but also from an economic point of view that adequate antibiotic treatment takes place as soon as possible, ideally starting with calculated initial treatment.</Pgraph><Pgraph>In addition, many studies comparing adequate and inadequate treatment have found in particular that patients who were proven to have infections with multidrug-resistant pathogens often did not received adequate initial treatment <TextLink reference="15"></TextLink>, <TextLink reference="18"></TextLink>, <TextLink reference="19"></TextLink>, <TextLink reference="20"></TextLink>, <TextLink reference="21"></TextLink>, <TextLink reference="22"></TextLink>, <TextLink reference="23"></TextLink>, <TextLink reference="24"></TextLink>, <TextLink reference="25"></TextLink>.</Pgraph><Pgraph>The resistance rate, i.e. the proportion of strains of a bacterial species that is resistant to one or more antimicrobial substances, has been identified as a factor that influences the cost-effectiveness of antibiotics <TextLink reference="26"></TextLink>. The effects were investigated in various decision analysis studies using the example of community-acquired pneumonia (CAP) <TextLink reference="27"></TextLink>, <TextLink reference="28"></TextLink>, <TextLink reference="29"></TextLink>. Sensitivity analyzes showed that taking the resistance rates of <Mark2>Streptococcus</Mark2> <Mark2>pneumoniae</Mark2> and <Mark2>Haemophilus</Mark2> <Mark2>influenzae</Mark2> into account in the selection of active agents resulted in a reduction of the failure rate of first-line treatment (thus removing the need for second-line therapy), hospital admissions and mortality.</Pgraph><Pgraph>In the treatment of life-threatening bacterial infections in which calculated antibiotic treatment is used initially, knowledge of the local, often even ward-specific pathogen spectrum and associated resistance situation is crucial. Therefore, it is essential that the resistance statistics are continuously compiled, evaluated and communicated to the clinicians by the microbiologists (or hospital hygienists). Microbiological diagnostics plays a special role in this. It has two important functions to fulfill:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Modification of initially calculated antibiotic treatment through microbiological findings and </ListItem><ListItem level="1">Providing data for determining the local pathogen and resistance spectrum against which future calculated antibiotic strategies will be targeted.</ListItem></UnorderedList></Pgraph><Pgraph>Especially regarding the first point it is important to obtain microbiological results as soon as possible. Here the use of fast and expensive diagnostic procedures can indeed be justified economically <TextLink reference="30"></TextLink>, <TextLink reference="31"></TextLink>. The aim is to initiate early escalation or de-escalation of calculated initial treatment by quickly determining the resistance status and thus to reduce the duration of possibly inadequate treatment with its associated negative consequences. Cost efficiency has been demonstrated in economic model calculations, for example for PCR-controlled calculated antibiotic treatment <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>.</Pgraph><Pgraph>In addition, it is important to consider patient-specific risk factors that indicate infection with a multidrug-resistant pathogen when selecting treatment. These primarily include previous treatment with antibiotics, colonization or infection with an MRE or pathogen with special resistance in the medical history, a hospital-acquired infection or a previous hospital stay, chronic immunosuppression (cancer, COPD, diabetes, MTX therapy with PCP, etc.) as well as stay on an intensive care ward (possibly with ventilation) and acute or chronic renal failure, to name only the most important <TextLink reference="34"></TextLink>, <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>, <TextLink reference="37"></TextLink>, <TextLink reference="38"></TextLink>, <TextLink reference="39"></TextLink>. The evaluation&#47;weighting of such risk factors is recommended, amongst others, in the selection of appropriate antibiotics for calculated initial treatment of pneumonia <TextLink reference="40"></TextLink>, <TextLink reference="41"></TextLink>, <TextLink reference="42"></TextLink>.</Pgraph><Pgraph>Failure to take account of the risks leads to poorer clinical outcomes and higher treatment costs. In these patients, the choice of an antibiotic which acts against multidrug-resistant pathogens in initial therapy may be the better choice clinically and economically. As soon as the pathogen is known, treatment should be adapted accordingly i.e. de-escalated. </Pgraph><Pgraph>The benefit of early consideration of multidrug-resistant pathogens in high-risk patients has so far only been shown in retrospective case-control studies but the authors nevertheless strongly recommend (A) this strategy.</Pgraph><SubHeadline>Rapid diagnostics with modern methods</SubHeadline><Pgraph>Precisely because misjudging the risk of a certain pathogen being present often leads to inadequate initial therapy and because pathogen identification by means of culture in clinical practice takes 48 hours or longer, the question arises as to whether newer diagnostic methods such as real-time PCR, MALDI-TOF or the PCR-based electron spray mass spectroscopy (PCR&#47;ESI-MS) <TextLink reference="43"></TextLink> can contribute to adequate initial therapy and a reduction in costs. Since these procedures are very expensive compared to conventional diagnostics, the question arises of when they are useful. Various authors have carried out investigations and selected different scientific approaches (expert assessment on the basis of test results <TextLink reference="44"></TextLink>, <TextLink reference="45"></TextLink>, modeling <TextLink reference="33"></TextLink>, before&#47;after <TextLink reference="30"></TextLink>, <TextLink reference="31"></TextLink>, <TextLink reference="46"></TextLink>). One work showed that rapid testing led to a reduction in the use of vancomycin and shortened the duration of hospital stays <TextLink reference="47"></TextLink>. After assessing the evidence for the present work, which deals explicitly with the economic effects of rapid diagnostics, the authors give a medium recommendation for this strategy (B).</Pgraph><SubHeadline>Antibiotic stewardship programme (ABS)</SubHeadline><Pgraph>Many measures to optimize antibiotic treatment can be subsumed under the term ABS. Here it was analyzed if there is evidence that extensive programs with measures such as</Pgraph><Pgraph><UnorderedList><ListItem level="1">creation of in-house recommendations,</ListItem><ListItem level="1">regular prescription analysis with ward rounds and continuous feedback,</ListItem><ListItem level="1">advice from ABS experts (such as infectiologists or clinical pharmacists), and</ListItem><ListItem level="1">restriction of certain antibiotic classes</ListItem></UnorderedList></Pgraph><Pgraph>are clinically and economically sensible. A number of international authors emphasize this clearly <TextLink reference="48"></TextLink>, <TextLink reference="49"></TextLink>, <TextLink reference="50"></TextLink>. In 2013 a Cochrane Review <TextLink reference="51"></TextLink> and an S3 guideline on this topic <TextLink reference="52"></TextLink> appeared. Overall, according to the authors, the evidence for the introduction of ABS programs and their clinical and economic benefits is very good and they are strongly recommended (A).</Pgraph><SubHeadline>Sequential therapy</SubHeadline><Pgraph>Parenteral-oral follow-up treatment (sequential therapy) gives the option to continue treatment initiated parenterally in hospital with oral (out-patient) administration. As a result, the duration of intravenous treatment is reduced without having a negative impact on the success of the treatment <TextLink reference="53"></TextLink>. In addition to reducing the risk of infusion-related infection and mobilizing the patient more quickly, there are a number of economic advantages that speak in favor of sequential therapy.</Pgraph><Pgraph>An early move to oral drug forms leads to a significant reduction in hospital stays, which can play a significant role in DRG flat-rate hospital remuneration systems. In a Europe-wide retrospective analysis of the treatment of MRSA-associated skin and soft tissue infections the team led by Nathwani and Eckmann found, for example, that the introduction of sequential therapy shortened hospital stays by 6.2 days on average with resultant potential savings of &#8364;2,000 per patient <TextLink reference="54"></TextLink>. Similar results were reported by Gray et al. with her study in 5 hospitals in the United Kingdom, where she found savings of &#163;363 per patient <TextLink reference="55"></TextLink>.</Pgraph><Pgraph>Other reasons for the economic superiority of sequential therapy over continuous parenteral therapy can be lower antibiotic costs and lower personnel costs for the preparation and administration of the parenteral antibiotics. The effects are not only evident in the clinical area but also in pre- and post-inpatient care.</Pgraph><Pgraph>Although there are mainly retrospective studies available on sequential therapy and its economic advantages, from an economic point of view the authors strongly recommend it (A).</Pgraph><SubHeadline>De-escalation</SubHeadline><Pgraph>In addition to sequential therapy, de-escalation can also contribute to optimizing the clinical economic balance. The aim is to replace calculated initial broad-spectrum antibiotic treatment with a more targeted one, i.e. to replace the initial substance with a similarly effective substance that however has a narrower spectrum. Prerequisites for this are:</Pgraph><Pgraph><UnorderedList><ListItem level="1">presence of specific and plausible microbiological findings </ListItem><ListItem level="1">clinical improvement (patient responded well to initial treatment)</ListItem></UnorderedList></Pgraph><Pgraph>By reducing the treatment spectrum and thus the antibiotic load, the development of resistances should be influenced favorably by minimizing the selection pressure. Patient safety is improved through fewer adverse drug reactions and superinfections <TextLink reference="52"></TextLink>. From an economic point of view this will result in (sometimes significant) savings in drug expenditure, not least by reducing the duration of treatment <TextLink reference="56"></TextLink>.</Pgraph><Pgraph>As with sequential therapy, the publications on the economic effects of de-escalation are predominantly either retrospective analyzes or secondary evaluations of clinical studies. Nevertheless, once again the authors express a strong recommendation (A).</Pgraph><SubHeadline>Therapeutic drug monitoring (TDM)</SubHeadline><Pgraph>It is important to determine drug levels, particularly in the case of antibiotics with a narrow therapeutic range, such as vancomycin but also in the case of prolonged treatment with beta-lactam antibiotics. For TDM in vancomycin it has been shown repeatedly that using TDM significantly reduces nephrotoxic complications and thus, despite the costs, leads to considerable savings through avoiding complications <TextLink reference="57"></TextLink>, <TextLink reference="58"></TextLink>.</Pgraph><Pgraph>An analysis of 200 intensive care patients with severe infections investigated various therapeutic strategies with piperacillin&#47;tazobactam. With an average total cost of &#8364;90.64 for a 7-day treatment with piperacillin&#47;tazobactam, in spite of the additional costs of therapeutic drug monitoring (TDM, &#8364;26.68) continuous administration of an individual dose was below the cost of intermittent bolus administration in line with the package insert recommendations of 3x 4.5 g (for complicated urinary tract infection, intra-abdominal infections, skin and soft tissue infections, &#8364;112.11) or 4x 4.5 g (for severe pneumonia, neutropenic adults with fever, in cases of suspected bacterial infection, &#8364;148.49). Reduced drug costs contributed to this result &#8211; &#8364;36.75 &#91;3x 4.5 g&#93;&#47;&#8364;49.00 &#91;4x 4.5 g&#93; bolus application versus &#8364;24.50 &#91;8 g (2&#8211;16 g), median (min, max)&#93; continuous application with TDM &#8211; about 30&#8211;50&#37;. Plus on the other hand the lower process costs (disposable items and working time for preparation and continuous application (&#8364;46.11&#47;&#8364;61.48 bolus application versus &#8364;24.42 continuous application) <TextLink reference="59"></TextLink>.</Pgraph><Pgraph>Although one of the studies on vancomycin was a randomized clinical study, overall there are relatively few studies on the economic aspects of TDM, the authors recommendation is a B-grade.</Pgraph><SubHeadline>Importance of process costs</SubHeadline><Pgraph>At the latest with the introduction of DRG, the analysis of their process costs and the resulting process optimization became imperative for hospitals. Here, it is important to consider the process of drug treatment from drug procurement through to administering it to a patient.</Pgraph><Pgraph>An important instrument for process optimization is the establishment of clinical treatment pathways and the creation of standard operating procedures (SOPs). With the help of these treatment paths&#47;process descriptions it is possible to document and ensure cost and quality of treatment. Part of the treatment pathways are standards in drug therapy. Anti-infective agents are an important drug group because of their major importance in terms of cost and also their significance for the quality and success of treatment. These treatment standards are also an important part of ABS programs. </Pgraph><Pgraph>An important criterion for the selection of appropriate anti-infective agents in the treatment pathways&#47;processes will be the economic-pharmacoeconomic analysis of alternative treatments from the perspective of a hospital. In addition to the purchase prices of drugs, consumption of other resources must also be taken into account.</Pgraph><Pgraph>It should also be questioned to what extent the anti-infective agent used satisfies aspects of quality management, quality assurance, process management, patient orientation and employee orientation. The following parameters are therefore included in such an analysis:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Personnel costs per application: under DRG conditions (increased output rates, reduced headcount), a reduction in the frequency of application should be considered positive. Also, the personnel costs incurred per application are an important criterion: they are given in the literature as being &#8364;2&#8211;4 or US&#36; per application <TextLink reference="60"></TextLink>, <TextLink reference="61"></TextLink>;</ListItem><ListItem level="1">the costs of the associated application aids such as syringes, cannulas, infusion sets, etc. In the literature, these costs are given depending on the type of application as being &#8364;1&#8211;4 <TextLink reference="61"></TextLink>;</ListItem><ListItem level="1">a lower error rate: Investigations and the resulting recommendations from English-speaking countries showed that the number of drug application errors decreases with the reduction of the frequency of application and the simplicity of preparation <TextLink reference="62"></TextLink>. The required number of steps in preparation must also be taken into account. So, whenever possible, ready-made preparations should be used;</ListItem><ListItem level="1">the possible likelihood of confusion; </ListItem><ListItem level="1">the cost of required monitoring but also the reduction in the use of anti-infective agents through monitoring.</ListItem></UnorderedList></Pgraph><Pgraph>The aim of this process and process cost analysis is to improve quality while optimizing costs. Cost optimization in this sense means that with the help of the described analysis, an anti-infective agent is chosen from amongst equally good active ingredients that has the lowest resource consumption. Due to the small number of studies that deal explicitly with litigation costs and error costs in antibiotic treatment, the authors give a Grade B recommendation.</Pgraph><SubHeadline>Economic consequences with increasing frequency of resistance</SubHeadline><Pgraph>From a clinical and ecological point of view, the risk of selection of antibiotic-resistant microorganisms should be minimized, as infections caused by multidrug-resistant or even pan-resistant bacteria are associated with a (considerably) increased mortality risk for patients. A number of publications on the health threat posed by antibiotic-resistant pathogens have also studied the associated costs. According to the State of the World&#8217;s Antibiotics report, the 23,000 patients who died as a result of an infection with resistant pathogens in the US led to health care costs of &#36;20 billion and &#36;35 billion in lost productivity <TextLink reference="63"></TextLink>. The 2014 WHO Global Report on Antibiotic Resistance Surveillance includes, amongst other things, a systematic literature review of the cost of infections with resistant microorganisms. This very sophisticated report comes to the conclusion that the increase of resistant pathogens has led to increased costs but that no global extrapolation can be made on the base of existing data <TextLink reference="64"></TextLink>. In particular, it is pointed out that the additional costs attributable to infections by resistant strains should be considered economically in comparison with infections by sensitive strains of a pathogen species in the same type of infection. For example there are several papers that have studied MRSA and MSSA infections economically. These gave attributable additional costs of &#8364;8,000 to &#8364;17,000 and US&#36;13,900 respectively <TextLink reference="65"></TextLink>, <TextLink reference="66"></TextLink>, <TextLink reference="67"></TextLink>, <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink>. Based on these amounts, it is easy to understand how the figures in the extrapolation above were reached. They appear quite realistic. Another report concludes that the number of deaths from resistant pathogens will rise from 700,000 worldwide today to <TextGroup><PlainText>10 m</PlainText></TextGroup>illion by 2050 if no further action is taken. In total, this would lead to a &#8211; global &#8211; total economic damage of US&#36;100 billion (100 trillions US-notation in the original) by 2050 <TextLink reference="70"></TextLink>. The authors acknowledge that first steps have been taken to tackle this global crisis. Intensified research, actions coordinated by WHO in 194 countries and advances in understanding the genetics of bacteria and, ultimately, the improvements in infection prevention in emerging economies are rays of hope.</Pgraph><Pgraph>In summary, it can be stated that resistance to antibiotics causes considerable direct financial and even greater economic damage. That is precisely why this topic should remain on the agenda in the future when discussing the economic aspects of antibiotic treatment.</Pgraph><SubHeadline>Further sources of information and their evaluation</SubHeadline><Pgraph>In Medline, there are also increasing indications of health economic works. The journals, which mainly publish articles on health economic issues, include &#8220;Health Economics and Quality Management&#8221; published by the German Society for Health Economics as well as international English-language journals such as &#8220;Health Economics&#8221;, &#8220;European Journal of Health Economics&#8221; and &#8220;Value in Health&#8221;.</Pgraph><Pgraph>It is a well-known problem that not only approval-related treatment studies but also many pharmacoeconomic studies are carried out in cooperation with the pharmaceutical industry. Such studies tend to present positive results for usually high-priced drug innovations and are often used as marketing tools for external sales visits or at specialist congresses. Also the choice of a method of analysis is often result-oriented or extensive and non-transparent model calculations are used. For the non-economist it is difficult to recognize this publication bias and to classify the significance of such studies. One option is to focus on reports from Health Technology Assessment (HTA) agencies such as the National Institute for Health and Clinical Excellence (<Hyperlink href="http:&#47;&#47;www.evidence.nhs.uk&#47;">http:&#47;&#47;www.evidence.nhs.uk&#47;</Hyperlink>), the Institute for Quality and Efficiency in Health (<Hyperlink href="https:&#47;&#47;www.iqwig.de&#47;">https:&#47;&#47;www.iqwig.de&#47;</Hyperlink>) or the Canadian Agency for Drugs and Technologies in Health (<Hyperlink href="http:&#47;&#47;www.cadth.ca&#47;">http:&#47;&#47;www.cadth.ca&#47;</Hyperlink>). In addition to a systematic presentation and qualitative assessment of the available evidence, these also include evaluations of the cost-effectiveness of pharmaceuticals and other medical technologies. These are based partly on existing studies and partly on their own economic studies. The increasing networking of international HTA agencies and a progressive standardization of assessment methods have an additional beneficial influence.</Pgraph><Pgraph>Studies and HTA reports are also presented in great detail in the database of the NHS Center for Review and Dissemination (<Hyperlink href="http:&#47;&#47;www.crd.york.ac.uk&#47;crdweb&#47;">http:&#47;&#47;www.crd.york.ac.uk&#47;crdweb&#47;</Hyperlink>). The NHS Economic Evaluation Database contains studies that can be found under Current Contents, Clinical Medicine, Medline, and CINAHL, as well as manual searches. Based on a scheme of approximately 30 criteria, the study objective, design of the clinical and economic part of the study as well as clinical and economic results are presented clearly and in detail. In addition, there is a brief evaluation of the study quality.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Anmerkung"> <MainHeadline>Anmerkung</MainHeadline><Pgraph>Dies ist das siebzehnte Kapitel der von der Paul-Ehrlich-Gesellschaft f&#252;r Chemotherapie e.V. (PEG) herausgegebenen S2k Leitlinie &#8222;Kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen &#8211; Update 2018&#8220; in der 2. aktualisierten Fassung.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Note"> <MainHeadline>Note</MainHeadline><Pgraph>This is the seventeenth chapter of the guideline &#8220;Calculated initial parenteral treatment of bacterial infections in adults &#8211; update 2018&#8221; in the 2<Superscript>nd</Superscript> updated version. The German guideline by the Paul-Ehrlich-Gesellschaft f&#252;r Chemotherapie 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 erkl&#228;ren, 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="1"> <RefAuthor>Shorr AF</RefAuthor> <RefAuthor>Haque N</RefAuthor> <RefAuthor>Taneja C</RefAuthor> <RefAuthor>Zervos M</RefAuthor> <RefAuthor>Lamerato L</RefAuthor> <RefAuthor>Kothari S</RefAuthor> <RefAuthor>Zilber S</RefAuthor> <RefAuthor>Donabedian S</RefAuthor> <RefAuthor>Perri MB</RefAuthor> <RefAuthor>Spalding J</RefAuthor> <RefAuthor>Oster G</RefAuthor> <RefTitle>Clinical and economic outcomes for patients with health care-associated Staphylococcus aureus pneumonia</RefTitle> <RefYear>2010</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>3258-62</RefPage> <RefTotal>Shorr AF, Haque N, Taneja C, Zervos M, Lamerato L, Kothari S, Zilber S, Donabedian S, Perri MB, Spalding J, Oster G. Clinical and economic outcomes for patients with health care-associated Staphylococcus aureus pneumonia. J Clin Microbiol. 2010 Sep;48(9):3258-62. DOI: 10.1128&#47;JCM.02529-09</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1128&#47;JCM.02529-09</RefLink> </Reference> <Reference refNo="2"> <RefAuthor>Ibrahim EH</RefAuthor> <RefAuthor>Sherman G</RefAuthor> <RefAuthor>Ward S</RefAuthor> <RefAuthor>Fraser VJ</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting</RefTitle> <RefYear>2000</RefYear> <RefJournal>Chest</RefJournal> <RefPage>146-55</RefPage> <RefTotal>Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000 Jul;118(1):146-55. DOI: 10.1378&#47;chest.118.1.146</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1378&#47;chest.118.1.146</RefLink> </Reference> <Reference refNo="3"> <RefAuthor>Retamar P</RefAuthor> <RefAuthor>L&#243;pez-Prieto MD</RefAuthor> <RefAuthor>Rodr&#237;guez-L&#243;pez F</RefAuthor> <RefAuthor>de Cueto M</RefAuthor> <RefAuthor>Garc&#237;a MV</RefAuthor> <RefAuthor>Gonz&#225;lez-Galan V</RefAuthor> <RefAuthor>Del Arco A</RefAuthor> <RefAuthor>P&#233;rez-Santos MJ</RefAuthor> <RefAuthor>T&#233;llez-P&#233;rez F</RefAuthor> <RefAuthor>Becerril-Carral B</RefAuthor> <RefAuthor>Mart&#237;n-Aspas A</RefAuthor> <RefAuthor>Arroyo A</RefAuthor> <RefAuthor>P&#233;rez-Cort&#233;s S</RefAuthor> <RefAuthor>Acosta F</RefAuthor> <RefAuthor>Florez C</RefAuthor> <RefAuthor>Le&#243;n-Ruiz L</RefAuthor> <RefAuthor>Mu&#241;oz-Medina L</RefAuthor> <RefAuthor>Rodr&#237;guez-Ba&#241;o J</RefAuthor> <RefAuthor> SAEI&#47;SAMPAC&#47;REIPI Bacteremia Group</RefAuthor> <RefTitle>Predictors of early mortality in very elderly patients with bacteremia: a prospective multicenter cohort</RefTitle> <RefYear>2014</RefYear> <RefJournal>Int J Infect Dis</RefJournal> <RefPage>83-7</RefPage> <RefTotal>Retamar P, L&#243;pez-Prieto MD, Rodr&#237;guez-L&#243;pez F, de Cueto M, Garc&#237;a MV, Gonz&#225;lez-Galan V, Del Arco A, P&#233;rez-Santos MJ, T&#233;llez-P&#233;rez F, Becerril-Carral B, Mart&#237;n-Aspas A, Arroyo A, P&#233;rez-Cort&#233;s S, Acosta F, Florez C, Le&#243;n-Ruiz L, Mu&#241;oz-Medina L, Rodr&#237;guez-Ba&#241;o J; SAEI&#47;SAMPAC&#47;REIPI Bacteremia Group. Predictors of early mortality in very elderly patients with bacteremia: a prospective multicenter cohort. Int J Infect Dis. 2014 Sep;26:83-7. DOI: 10.1016&#47;j.ijid.2014.04.029</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1016&#47;j.ijid.2014.04.029</RefLink> </Reference> <Reference refNo="4"> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients</RefTitle> <RefYear>2000</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>S131-8</RefPage> <RefTotal>Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis. 2000 Sep;31 Suppl 4:S131-8. DOI: 10.1086&#47;314079</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1086&#47;314079</RefLink> </Reference> <Reference refNo="5"> <RefAuthor>Kumar A</RefAuthor> <RefTitle>Optimizing antimicrobial therapy in sepsis and septic shock</RefTitle> <RefYear>2009</RefYear> <RefJournal>Crit Care Clin</RefJournal> <RefPage>733-51, viii</RefPage> <RefTotal>Kumar A. Optimizing antimicrobial therapy in sepsis and septic shock. Crit Care Clin. 2009 Oct;25(4):733-51, viii. DOI: 10.1016&#47;j.ccc.2009.08.004</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1016&#47;j.ccc.2009.08.004</RefLink> </Reference> <Reference refNo="6"> <RefAuthor>Chong YP</RefAuthor> <RefAuthor>Bae IG</RefAuthor> <RefAuthor>Lee SR</RefAuthor> <RefAuthor>Chung JW</RefAuthor> <RefAuthor>Jun JB</RefAuthor> <RefAuthor>Choo EJ</RefAuthor> <RefAuthor>Moon SY</RefAuthor> <RefAuthor>Lee MS</RefAuthor> <RefAuthor>Jeon MH</RefAuthor> <RefAuthor>Song EH</RefAuthor> <RefAuthor>Lee EJ</RefAuthor> <RefAuthor>Park SY</RefAuthor> <RefAuthor>Kim YS</RefAuthor> <RefTitle>Clinical and economic consequences of failure of initial antibiotic therapy for patients with community-onset complicated intra-abdominal infections</RefTitle> <RefYear>2015</RefYear> <RefJournal>PLoS One</RefJournal> <RefPage>e0119956</RefPage> <RefTotal>Chong YP, Bae IG, Lee SR, Chung JW, Jun JB, Choo EJ, Moon SY, Lee MS, Jeon MH, Song EH, Lee EJ, Park SY, Kim YS. Clinical and economic consequences of failure of initial antibiotic therapy for patients with community-onset complicated intra-abdominal infections. PLoS One. 2015 Apr 24;10(4):e0119956. DOI: 10.1371&#47;journal.pone.0119956</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1371&#47;journal.pone.0119956</RefLink> </Reference> <Reference refNo="7"> <RefAuthor>Lodise TP</RefAuthor> <RefAuthor>McKinnon PS</RefAuthor> <RefAuthor>Swiderski L</RefAuthor> <RefAuthor>Rybak MJ</RefAuthor> <RefTitle>Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia</RefTitle> <RefYear>2003</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>1418-23</RefPage> <RefTotal>Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis. 2003 Jun;36(11):1418-23. DOI: 10.1086&#47;375057</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1086&#47;375057</RefLink> </Reference> <Reference refNo="8"> <RefAuthor>Davey PG</RefAuthor> <RefAuthor>Marwick C</RefAuthor> <RefTitle>Appropriate vs. inappropriate antimicrobial therapy</RefTitle> <RefYear>2008</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>15-21</RefPage> <RefTotal>Davey PG, Marwick C. Appropriate vs. inappropriate antimicrobial therapy. Clin Microbiol Infect. 2008 Apr;14 Suppl 3:15-21. DOI: 10.1111&#47;j.1469-0691.2008.01959.x</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1111&#47;j.1469-0691.2008.01959.x</RefLink> </Reference> <Reference refNo="9"> <RefAuthor>Kuti EL</RefAuthor> <RefAuthor>Patel AA</RefAuthor> <RefAuthor>Coleman CI</RefAuthor> <RefTitle>Impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumonia and blood stream infection: a meta-analysis</RefTitle> <RefYear>2008</RefYear> <RefJournal>J Crit Care</RefJournal> <RefPage>91-100</RefPage> <RefTotal>Kuti EL, Patel AA, Coleman CI. Impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumonia and blood stream infection: a meta-analysis. J Crit Care. 2008 Mar;23(1):91-100. DOI: 10.1016&#47;j.jcrc.2007.08.007</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1016&#47;j.jcrc.2007.08.007</RefLink> </Reference> <Reference refNo="10"> <RefAuthor>Singh N</RefAuthor> <RefAuthor>Rogers P</RefAuthor> <RefAuthor>Atwood CW</RefAuthor> <RefAuthor>Wagener MM</RefAuthor> <RefAuthor>Yu VL</RefAuthor> <RefTitle>Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription</RefTitle> <RefYear>2000</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>505-11</RefPage> <RefTotal>Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):505-11. DOI: 10.1164&#47;ajrccm.162.2.9909095</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1164&#47;ajrccm.162.2.9909095</RefLink> </Reference> <Reference refNo="11"> <RefAuthor>Marrie TJ</RefAuthor> <RefAuthor>Lau CY</RefAuthor> <RefAuthor>Wheeler SL</RefAuthor> <RefAuthor>Wong CJ</RefAuthor> <RefAuthor>Vandervoort MK</RefAuthor> <RefAuthor>Feagan BG</RefAuthor> <RefTitle>A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL Study Investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin</RefTitle> <RefYear>2000</RefYear> <RefJournal>JAMA</RefJournal> <RefPage>749-55</RefPage> <RefTotal>Marrie TJ, Lau CY, Wheeler SL, Wong CJ, Vandervoort MK, Feagan BG. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL Study Investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin. JAMA. 2000 Feb;283(6):749-55. DOI: 10.1001&#47;jama.283.6.749</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1001&#47;jama.283.6.749</RefLink> </Reference> <Reference refNo="12"> <RefAuthor>Men&#233;ndez R</RefAuthor> <RefAuthor>Torres A</RefAuthor> <RefAuthor>Reyes S</RefAuthor> <RefAuthor>Zalacain R</RefAuthor> <RefAuthor>Capelastegui A</RefAuthor> <RefAuthor>Aspa J</RefAuthor> <RefAuthor>Border&#237;as L</RefAuthor> <RefAuthor>Mart&#237;n-Villasclaras JJ</RefAuthor> <RefAuthor>Bello S</RefAuthor> <RefAuthor>Alfageme I</RefAuthor> <RefAuthor>de Castro FR</RefAuthor> <RefAuthor>Rello J</RefAuthor> <RefAuthor>Molinos L</RefAuthor> <RefAuthor>Ruiz-Manzano J</RefAuthor> <RefTitle>Initial management of pneumonia and sepsis: factors associated with improved outcome</RefTitle> <RefYear>2012</RefYear> <RefJournal>Eur Respir J</RefJournal> <RefPage>156-62</RefPage> <RefTotal>Men&#233;ndez R, Torres A, Reyes S, Zalacain R, Capelastegui A, Aspa J, Border&#237;as L, Mart&#237;n-Villasclaras JJ, Bello S, Alfageme I, de Castro FR, Rello J, Molinos L, Ruiz-Manzano J. Initial management of pneumonia and sepsis: factors associated with improved outcome. Eur Respir J. 2012 Jan;39(1):156-62. DOI: 10.1183&#47;09031936.00188710</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1183&#47;09031936.00188710</RefLink> </Reference> <Reference refNo="13"> <RefAuthor>Wawrzeniak IC</RefAuthor> <RefAuthor>Loss SH</RefAuthor> <RefAuthor>Moraes MC</RefAuthor> <RefAuthor>De La Vega FL</RefAuthor> <RefAuthor>Victorino JA</RefAuthor> <RefTitle>Could a protocol based on early goal-directed therapy improve outcomes in patients with severe sepsis and septic shock in the Intensive Care Unit setting&#63;</RefTitle> <RefYear>2015</RefYear> <RefJournal>Indian J Crit Care Med</RefJournal> <RefPage>159-65</RefPage> <RefTotal>Wawrzeniak IC, Loss SH, Moraes MC, De La Vega FL, Victorino JA. Could a protocol based on early goal-directed therapy improve outcomes in patients with severe sepsis and septic shock in the Intensive Care Unit setting&#63;. Indian J Crit Care Med. 2015 Mar;19(3):159-65. DOI: 10.4103&#47;0972-5229.152759</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.4103&#47;0972-5229.152759</RefLink> </Reference> <Reference refNo="40"> <RefAuthor>Wilke M</RefAuthor> <RefAuthor>Grube RF</RefAuthor> <RefAuthor>Bodmann KF</RefAuthor> <RefTitle>Guideline-adherent initial intravenous antibiotic therapy for hospital-acquired&#47;ventilator-associated pneumonia is clinically superior, saves lives and is cheaper than non guideline adherent therapy</RefTitle> <RefYear>2011</RefYear> <RefJournal>Eur J Med Res</RefJournal> <RefPage>315-23</RefPage> <RefTotal>Wilke M, Grube RF, Bodmann KF. Guideline-adherent initial intravenous antibiotic therapy for hospital-acquired&#47;ventilator-associated pneumonia is clinically superior, saves lives and is cheaper than non guideline adherent therapy. Eur J Med Res. 2011 Jul;16(7):315-23. DOI: 10.1186&#47;2047-783X-16-7-315</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1186&#47;2047-783X-16-7-315</RefLink> </Reference> <Reference refNo="14"> <RefAuthor>Rello J</RefAuthor> <RefAuthor>Ulldemolins M</RefAuthor> <RefAuthor>Lisboa T</RefAuthor> <RefAuthor>Koulenti D</RefAuthor> <RefAuthor>Ma&#241;ez R</RefAuthor> <RefAuthor>Martin-Loeches I</RefAuthor> <RefAuthor>De Waele JJ</RefAuthor> <RefAuthor>Putensen C</RefAuthor> <RefAuthor>Guven M</RefAuthor> <RefAuthor>Deja M</RefAuthor> <RefAuthor>Diaz E</RefAuthor> <RefAuthor> EU-VAP&#47;CAP Study Group</RefAuthor> <RefTitle>Determinants of prescription and choice of empirical therapy for hospital-acquired and ventilator-associated pneumonia</RefTitle> <RefYear>2011</RefYear> <RefJournal>Eur Respir J</RefJournal> <RefPage>1332-9</RefPage> <RefTotal>Rello J, Ulldemolins M, Lisboa T, Koulenti D, Ma&#241;ez R, Martin-Loeches I, De Waele JJ, Putensen C, Guven M, Deja M, Diaz E; EU-VAP&#47;CAP Study Group. Determinants of prescription and choice of empirical therapy for hospital-acquired and ventilator-associated pneumonia. Eur Respir J. 2011 Jun;37(6):1332-9. DOI: 10.1183&#47;09031936.00093010</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1183&#47;09031936.00093010</RefLink> </Reference> <Reference refNo="15"> <RefAuthor>Micek ST</RefAuthor> <RefAuthor>Welch EC</RefAuthor> <RefAuthor>Khan J</RefAuthor> <RefAuthor>Pervez M</RefAuthor> <RefAuthor>Doherty JA</RefAuthor> <RefAuthor>Reichley RM</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis</RefTitle> <RefYear>2010</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>1742-8</RefPage> <RefTotal>Micek ST, Welch EC, Khan J, Pervez M, Doherty JA, Reichley RM, Kollef MH. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother. 2010 May;54(5):1742-8. DOI: 10.1128&#47;AAC.01365-09</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1128&#47;AAC.01365-09</RefLink> </Reference> <Reference refNo="16"> <RefAuthor>Meyer E</RefAuthor> <RefAuthor>Buttler J</RefAuthor> <RefAuthor>Schneider C</RefAuthor> <RefAuthor>Strehl E</RefAuthor> <RefAuthor>Schroeren-Boersch B</RefAuthor> <RefAuthor>Gastmeier P</RefAuthor> <RefAuthor>Ruden H</RefAuthor> <RefAuthor>Zentner J</RefAuthor> <RefAuthor>Daschner FD</RefAuthor> <RefAuthor>Schwab F</RefAuthor> <RefTitle>Modified guidelines impact on antibiotic use and costs: duration of treatment for pneumonia in a neurosurgical ICU is reduced</RefTitle> <RefYear>2007</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>1148-54</RefPage> <RefTotal>Meyer E, Buttler J, Schneider C, Strehl E, Schroeren-Boersch B, Gastmeier P, Ruden H, Zentner J, Daschner FD, Schwab F. Modified guidelines impact on antibiotic use and costs: duration of treatment for pneumonia in a neurosurgical ICU is reduced. J Antimicrob Chemother. 2007 Jun;59(6):1148-54. DOI: 10.1093&#47;jac&#47;dkm088</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;jac&#47;dkm088</RefLink> </Reference> <Reference refNo="17"> <RefAuthor>Garnacho-Montero J</RefAuthor> <RefAuthor>Ortiz-Leyba C</RefAuthor> <RefAuthor>Herrera-Melero I</RefAuthor> <RefAuthor>Aldab&#243;-Pall&#225;s T</RefAuthor> <RefAuthor>Cayuela-Dominguez A</RefAuthor> <RefAuthor>Marquez-Vacaro JA</RefAuthor> <RefAuthor>Carbajal-Guerrero J</RefAuthor> <RefAuthor>Garcia-Garmendia JL</RefAuthor> <RefTitle>Mortality and morbidity attributable to inadequate empirical antimicrobial therapy in patients admitted to the ICU with sepsis: a matched cohort study</RefTitle> <RefYear>2008</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>436-41</RefPage> <RefTotal>Garnacho-Montero J, Ortiz-Leyba C, Herrera-Melero I, Aldab&#243;-Pall&#225;s T, Cayuela-Dominguez A, Marquez-Vacaro JA, Carbajal-Guerrero J, Garcia-Garmendia JL. Mortality and morbidity attributable to inadequate empirical antimicrobial therapy in patients admitted to the ICU with sepsis: a matched cohort study. J Antimicrob Chemother. 2008 Feb;61(2):436-41. DOI: 10.1093&#47;jac&#47;dkm460</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;jac&#47;dkm460</RefLink> </Reference> <Reference refNo="18"> <RefAuthor>Mauldin PD</RefAuthor> <RefAuthor>Salgado CD</RefAuthor> <RefAuthor>Hansen IS</RefAuthor> <RefAuthor>Durup DT</RefAuthor> <RefAuthor>Bosso JA</RefAuthor> <RefTitle>Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant gram-negative bacteria</RefTitle> <RefYear>2010</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>109-15</RefPage> <RefTotal>Mauldin PD, Salgado CD, Hansen IS, Durup DT, Bosso JA. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant gram-negative bacteria. Antimicrob Agents Chemother. 2010 Jan;54(1):109-15. DOI: 10.1128&#47;AAC.01041-09</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1128&#47;AAC.01041-09</RefLink> </Reference> <Reference refNo="19"> <RefAuthor>Marquet K</RefAuthor> <RefAuthor>Liesenborgs A</RefAuthor> <RefAuthor>Bergs J</RefAuthor> <RefAuthor>Vleugels A</RefAuthor> <RefAuthor>Claes N</RefAuthor> <RefTitle>Incidence and outcome of inappropriate in-hospital empiric antibiotics for severe infection: a systematic review and meta-analysis</RefTitle> <RefYear>2015</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>63</RefPage> <RefTotal>Marquet K, Liesenborgs A, Bergs J, Vleugels A, Claes N. Incidence and outcome of inappropriate in-hospital empiric antibiotics for severe infection: a systematic review and meta-analysis. Crit Care. 2015 Feb;19:63. DOI: 10.1186&#47;s13054-015-0795-y</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1186&#47;s13054-015-0795-y</RefLink> </Reference> <Reference refNo="20"> <RefAuthor>MacVane SH</RefAuthor> <RefAuthor>Tuttle LO</RefAuthor> <RefAuthor>Nicolau DP</RefAuthor> <RefTitle>Impact of extended-spectrum &#946;-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection</RefTitle> <RefYear>2014</RefYear> <RefJournal>J Hosp Med</RefJournal> <RefPage>232-8</RefPage> <RefTotal>MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum &#946;-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. 2014 Apr;9(4):232-8. DOI: 10.1002&#47;jhm.2157</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1002&#47;jhm.2157</RefLink> </Reference> <Reference refNo="21"> <RefAuthor>Cheah AL</RefAuthor> <RefAuthor>Spelman T</RefAuthor> <RefAuthor>Liew D</RefAuthor> <RefAuthor>Peel T</RefAuthor> <RefAuthor>Howden BP</RefAuthor> <RefAuthor>Spelman D</RefAuthor> <RefAuthor>Grayson ML</RefAuthor> <RefAuthor>Nation RL</RefAuthor> <RefAuthor>Kong DC</RefAuthor> <RefTitle>Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization</RefTitle> <RefYear>2013</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>E181-9</RefPage> <RefTotal>Cheah AL, Spelman T, Liew D, Peel T, Howden BP, Spelman D, Grayson ML, Nation RL, Kong DC. Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization. Clin Microbiol Infect. 2013 Apr;19(4):E181-9. DOI: 10.1111&#47;1469-0691.12132</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1111&#47;1469-0691.12132</RefLink> </Reference> <Reference refNo="22"> <RefAuthor>Micek S</RefAuthor> <RefAuthor>Johnson MT</RefAuthor> <RefAuthor>Reichley R</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>An institutional perspective on the impact of recent antibiotic exposure on length of stay and hospital costs for patients with gram-negative sepsis</RefTitle> <RefYear>2012</RefYear> <RefJournal>BMC Infect Dis</RefJournal> <RefPage>56</RefPage> <RefTotal>Micek S, Johnson MT, Reichley R, Kollef MH. An institutional perspective on the impact of recent antibiotic exposure on length of stay and hospital costs for patients with gram-negative sepsis. BMC Infect Dis. 2012 Mar;12:56. DOI: 10.1186&#47;1471-2334-12-56</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1186&#47;1471-2334-12-56</RefLink> </Reference> <Reference refNo="23"> <RefAuthor>Shorr AF</RefAuthor> <RefAuthor>Micek ST</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Inappropriate therapy for methicillin-resistant Staphylococcus aureus: resource utilization and cost implications</RefTitle> <RefYear>2008</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2335-40</RefPage> <RefTotal>Shorr AF, Micek ST, Kollef MH. Inappropriate therapy for methicillin-resistant Staphylococcus aureus: resource utilization and cost implications. Crit Care Med. 2008 Aug;36(8):2335-40. DOI: 10.1097&#47;CCM.0b013e31818103ea</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1097&#47;CCM.0b013e31818103ea</RefLink> </Reference> <Reference refNo="24"> <RefAuthor>Hirsch EB</RefAuthor> <RefAuthor>Tam VH</RefAuthor> <RefTitle>Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes</RefTitle> <RefYear>2010</RefYear> <RefJournal>Expert Rev Pharmacoecon Outcomes Res</RefJournal> <RefPage>441-51</RefPage> <RefTotal>Hirsch EB, Tam VH. Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes. Expert Rev Pharmacoecon Outcomes Res. 2010 Aug;10(4):441-51. DOI: 10.1586&#47;erp.10.49</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1586&#47;erp.10.49</RefLink> </Reference> <Reference refNo="25"> <RefAuthor>Heyland DK</RefAuthor> <RefAuthor>Cook DJ</RefAuthor> <RefAuthor>Griffith L</RefAuthor> <RefAuthor>Keenan SP</RefAuthor> <RefAuthor>Brun-Buisson C</RefAuthor> <RefTitle>The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group</RefTitle> <RefYear>1999</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>1249-56</RefPage> <RefTotal>Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Buisson C. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1249-56. DOI: 10.1164&#47;ajrccm.159.4.9807050</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1164&#47;ajrccm.159.4.9807050</RefLink> </Reference> <Reference refNo="26"> <RefAuthor>Simoens S</RefAuthor> <RefTitle>Factors affecting the cost effectiveness of antibiotics</RefTitle> <RefYear>2011</RefYear> <RefJournal>Chemother Res Pract</RefJournal> <RefPage>249867</RefPage> <RefTotal>Simoens S. Factors affecting the cost effectiveness of antibiotics. Chemother Res Pract. 2011;2011:249867. DOI: 10.1155&#47;2011&#47;249867</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1155&#47;2011&#47;249867</RefLink> </Reference> <Reference refNo="27"> <RefAuthor>Sabes-Figuera R</RefAuthor> <RefAuthor>Seg&#250; JL</RefAuthor> <RefAuthor>Puig-Junoy J</RefAuthor> <RefAuthor>Torres A</RefAuthor> <RefTitle>Influence of bacterial resistances on the efficiency of antibiotic treatments for community-acquired pneumonia</RefTitle> <RefYear>2008</RefYear> <RefJournal>Eur J Health Econ</RefJournal> <RefPage>23-32</RefPage> <RefTotal>Sabes-Figuera R, Seg&#250; JL, Puig-Junoy J, Torres A. Influence of bacterial resistances on the efficiency of antibiotic treatments for community-acquired pneumonia. Eur J Health Econ. 2008 Feb;9(1):23-32. DOI: 10.1007&#47;s10198-006-0019-0</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1007&#47;s10198-006-0019-0</RefLink> </Reference> <Reference refNo="28"> <RefAuthor>Martin M</RefAuthor> <RefAuthor>Quilici S</RefAuthor> <RefAuthor>File T</RefAuthor> <RefAuthor>Garau J</RefAuthor> <RefAuthor>Kureishi A</RefAuthor> <RefAuthor>Kubin M</RefAuthor> <RefTitle>Cost-effectiveness of empirical prescribing of antimicrobials in community-acquired pneumonia in three countries in the presence of resistance</RefTitle> <RefYear>2007</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>977-89</RefPage> <RefTotal>Martin M, Quilici S, File T, Garau J, Kureishi A, Kubin M. Cost-effectiveness of empirical prescribing of antimicrobials in community-acquired pneumonia in three countries in the presence of resistance. J Antimicrob Chemother. 2007 May;59(5):977-89. DOI: 10.1093&#47;jac&#47;dkm033</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;jac&#47;dkm033</RefLink> </Reference> <Reference refNo="29"> <RefAuthor>Martin M</RefAuthor> <RefAuthor>Moore L</RefAuthor> <RefAuthor>Quilici S</RefAuthor> <RefAuthor>Decramer M</RefAuthor> <RefAuthor>Simoens S</RefAuthor> <RefTitle>A cost-effectiveness analysis of antimicrobial treatment of community-acquired pneumonia taking into account resistance in Belgium</RefTitle> <RefYear>2008</RefYear> <RefJournal>Curr Med Res Opin</RefJournal> <RefPage>737-51</RefPage> <RefTotal>Martin M, Moore L, Quilici S, Decramer M, Simoens S. A cost-effectiveness analysis of antimicrobial treatment of community-acquired pneumonia taking into account resistance in Belgium. Curr Med Res Opin. 2008 Mar;24(3):737-51. DOI: 10.1185&#47;030079908X273336</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1185&#47;030079908X273336</RefLink> </Reference> <Reference refNo="30"> <RefAuthor>Perez KK</RefAuthor> <RefAuthor>Olsen RJ</RefAuthor> <RefAuthor>Musick WL</RefAuthor> <RefAuthor>Cernoch PL</RefAuthor> <RefAuthor>Davis JR</RefAuthor> <RefAuthor>Peterson LE</RefAuthor> <RefAuthor>Musser JM</RefAuthor> <RefTitle>Integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibiotic-resistant Gram-negative bacteremia</RefTitle> <RefYear>2014</RefYear> <RefJournal>J Infect</RefJournal> <RefPage>216-25</RefPage> <RefTotal>Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Peterson LE, Musser JM. Integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibiotic-resistant Gram-negative bacteremia. J Infect. 2014 Sep;69(3):216-25. DOI: 10.1016&#47;j.jinf.2014.05.005</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1016&#47;j.jinf.2014.05.005</RefLink> </Reference> <Reference refNo="31"> <RefAuthor>Perez KK</RefAuthor> <RefAuthor>Olsen RJ</RefAuthor> <RefAuthor>Musick WL</RefAuthor> <RefAuthor>Cernoch PL</RefAuthor> <RefAuthor>Davis JR</RefAuthor> <RefAuthor>Land GA</RefAuthor> <RefAuthor>Peterson LE</RefAuthor> <RefAuthor>Musser JM</RefAuthor> <RefTitle>Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs</RefTitle> <RefYear>2013</RefYear> <RefJournal>Arch Pathol Lab Med</RefJournal> <RefPage>1247-54</RefPage> <RefTotal>Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Land GA, Peterson LE, Musser JM. Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. Arch Pathol Lab Med. 2013 Sep;137(9):1247-54. DOI: 10.5858&#47;arpa.2012-0651-OA</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.5858&#47;arpa.2012-0651-OA</RefLink> </Reference> <Reference refNo="32"> <RefAuthor>Brown J</RefAuthor> <RefAuthor>Paladino JA</RefAuthor> <RefTitle>Impact of rapid methicillin-resistant Staphylococcus aureus polymerase chain reaction testing on mortality and cost effectiveness in hospitalized patients with bacteraemia: a decision model</RefTitle> <RefYear>2010</RefYear> <RefJournal>Pharmacoeconomics</RefJournal> <RefPage>567-75</RefPage> <RefTotal>Brown J, Paladino JA. Impact of rapid methicillin-resistant Staphylococcus aureus polymerase chain reaction testing on mortality and cost effectiveness in hospitalized patients with bacteraemia: a decision model. Pharmacoeconomics. 2010;28(7):567-75. DOI: 10.2165&#47;11533020-000000000-00000</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.2165&#47;11533020-000000000-00000</RefLink> </Reference> <Reference refNo="33"> <RefAuthor>H&#252;bner C</RefAuthor> <RefAuthor>H&#252;bner NO</RefAuthor> <RefAuthor>Kramer A</RefAuthor> <RefAuthor>Fle&#223;a S</RefAuthor> <RefTitle>Cost-analysis of PCR-guided pre-emptive antibiotic treatment of Staphylococcus aureus infections: an analytic decision model</RefTitle> <RefYear>2012</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>3065-72</RefPage> <RefTotal>H&#252;bner C, H&#252;bner NO, Kramer A, Fle&#223;a S. Cost-analysis of PCR-guided pre-emptive antibiotic treatment of Staphylococcus aureus infections: an analytic decision model. Eur J Clin Microbiol Infect Dis. 2012 Nov;31(11):3065-72. DOI: 10.1007&#47;s10096-012-1666-y</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1007&#47;s10096-012-1666-y</RefLink> </Reference> <Reference refNo="34"> <RefAuthor>Aliberti S</RefAuthor> <RefAuthor>Di Pasquale M</RefAuthor> <RefAuthor>Zanaboni AM</RefAuthor> <RefAuthor>Cosentini R</RefAuthor> <RefAuthor>Brambilla AM</RefAuthor> <RefAuthor>Seghezzi S</RefAuthor> <RefAuthor>Tarsia P</RefAuthor> <RefAuthor>Mantero M</RefAuthor> <RefAuthor>Blasi F</RefAuthor> <RefTitle>Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia</RefTitle> <RefYear>2012</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>470-8</RefPage> <RefTotal>Aliberti S, Di Pasquale M, Zanaboni AM, Cosentini R, Brambilla AM, Seghezzi S, Tarsia P, Mantero M, Blasi F. Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia. Clin Infect Dis. 2012 Feb;54(4):470-8. DOI: 10.1093&#47;cid&#47;cir840</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;cid&#47;cir840</RefLink> </Reference> <Reference refNo="35"> <RefAuthor>American Thoracic Society</RefAuthor> <RefAuthor> Infectious Diseases Society of America</RefAuthor> <RefTitle>Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia</RefTitle> <RefYear>2005</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>388-416</RefPage> <RefTotal>American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005 Feb;171(4):388-416. DOI: 10.1164&#47;rccm.200405-644ST</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1164&#47;rccm.200405-644ST</RefLink> </Reference> <Reference refNo="36"> <RefAuthor>Bowman N</RefAuthor> <RefAuthor>Goswami N</RefAuthor> <RefAuthor>Lippincott CK</RefAuthor> <RefAuthor>Vinikoor MJ</RefAuthor> <RefAuthor>Miller WC</RefAuthor> <RefTitle>Clinical scoring for risk of resistant organisms in pneumonia: right idea, wrong interpretation</RefTitle> <RefYear>2012</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>749-50</RefPage> <RefTotal>Bowman N, Goswami N, Lippincott CK, Vinikoor MJ, Miller WC. Clinical scoring for risk of resistant organisms in pneumonia: right idea, wrong interpretation. Clin Infect Dis. 2012 Sep;55(5):749-50. DOI: 10.1093&#47;cid&#47;cis532</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;cid&#47;cis532</RefLink> </Reference> <Reference refNo="37"> <RefAuthor>Dalhoff K</RefAuthor> <RefAuthor>Abele-Horn M</RefAuthor> <RefAuthor>Andreas S</RefAuthor> <RefAuthor>Bauer T</RefAuthor> <RefAuthor>von Baum H</RefAuthor> <RefAuthor>Deja M</RefAuthor> <RefAuthor>Ewig S</RefAuthor> <RefAuthor>Gastmeier P</RefAuthor> <RefAuthor>Gatermann S</RefAuthor> <RefAuthor>Gerlach H</RefAuthor> <RefAuthor>Grabein B</RefAuthor> <RefAuthor>H&#246;ffken G</RefAuthor> <RefAuthor>Kern WV</RefAuthor> <RefAuthor>Kramme E</RefAuthor> <RefAuthor>Lange C</RefAuthor> <RefAuthor>Lorenz J</RefAuthor> <RefAuthor>Mayer K</RefAuthor> <RefAuthor>Nachtigall I</RefAuthor> <RefAuthor>Pletz M</RefAuthor> <RefAuthor>Rohde G</RefAuthor> <RefAuthor>Rosseau S</RefAuthor> <RefAuthor>Schaaf B</RefAuthor> <RefAuthor>Schaumann R</RefAuthor> <RefAuthor>Schreiter D</RefAuthor> <RefAuthor>Sch&#252;tte H</RefAuthor> <RefAuthor>Seifert H</RefAuthor> <RefAuthor>Sitter H</RefAuthor> <RefAuthor>Spies C</RefAuthor> <RefAuthor>Welte T</RefAuthor> <RefAuthor> German Society for Anaesthesiology and Intensive Care Medicine</RefAuthor> <RefAuthor> German Society for Infectious Diseases</RefAuthor> <RefAuthor> German Society for Hygiene and Microbiology</RefAuthor> <RefAuthor> German Respiratory Society</RefAuthor> <RefAuthor> Paul-Ehrlich-Society for Chemotherapy</RefAuthor> <RefTitle>Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie. S-3 Leitlinie der Deutschen Gesellschaft fur An&#228;sthesiologie und Intensivmedizin e.V., der Deutschen Gesellschaft fur Infektiologie e.V., der Deutschen Gesellschaft fur Hygiene und Mikrobiologie e.V., der Deutschen Gesellschaft f&#252;r Pneumologie und Beatmungsmedizin e.V. und der Paul-Ehrlich-Gesellschaft fur Chemotherapie e.V.</RefTitle> <RefYear>2012</RefYear> <RefJournal>Pneumologie</RefJournal> <RefPage>707-65</RefPage> <RefTotal>Dalhoff K, Abele-Horn M, Andreas S, Bauer T, von Baum H, Deja M, Ewig S, Gastmeier P, Gatermann S, Gerlach H, Grabein B, H&#246;ffken G, Kern WV, Kramme E, Lange C, Lorenz J, Mayer K, Nachtigall I, Pletz M, Rohde G, Rosseau S, Schaaf B, Schaumann R, Schreiter D, Sch&#252;tte H, Seifert H, Sitter H, Spies C, Welte T; German Society for Anaesthesiology and Intensive Care Medicine; German Society for Infectious Diseases; German Society for Hygiene and Microbiology; German Respiratory Society; Paul-Ehrlich-Society for Chemotherapy. Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie. S-3 Leitlinie der Deutschen Gesellschaft fur An&#228;sthesiologie und Intensivmedizin e.V., der Deutschen Gesellschaft fur Infektiologie e.V., der Deutschen Gesellschaft fur Hygiene und Mikrobiologie e.V., der Deutschen Gesellschaft f&#252;r Pneumologie und Beatmungsmedizin e.V. und der Paul-Ehrlich-Gesellschaft fur Chemotherapie e.V. &#91;Epidemiology, diagnosis and treatment of adult patients with nosocomial pneumonia. S-3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy&#93;. Pneumologie. 2012 Dec;66(12):707-65. DOI: 10.1055&#47;s-0032-1325924</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1055&#47;s-0032-1325924</RefLink> </Reference> <Reference refNo="38"> <RefAuthor>Bodmann K-F</RefAuthor> <RefAuthor>Lorenz J</RefAuthor> <RefAuthor>Bauer TT</RefAuthor> <RefAuthor>Ewig S</RefAuthor> <RefAuthor>Trautmann M</RefAuthor> <RefAuthor>Vogel F</RefAuthor> <RefTitle>Nosokomiale Pneumonie: Pr&#228;vention, Diagnostik und Therapie: Ein Konsensuspapier der Paul-Ehrlich-Gesellschaft f&#252;r Chemotherapie (PEG) und der Deutschen Gesellschaft f&#252;r Pneumologie (DGP) unter Mitarbeit von Experten der Deutschen Gesellschaft f&#252;r An&#228;sthesiologie und Intensivmedizin (DGAI) &#8211; PEG Emfehlungen</RefTitle> <RefYear>2003</RefYear> <RefJournal>Chemother J</RefJournal> <RefPage>33-44</RefPage> <RefTotal>Bodmann K-F, Lorenz J, Bauer TT, Ewig S, Trautmann M, Vogel F. Nosokomiale Pneumonie: Pr&#228;vention, Diagnostik und Therapie: Ein Konsensuspapier der Paul-Ehrlich-Gesellschaft f&#252;r Chemotherapie (PEG) und der Deutschen Gesellschaft f&#252;r Pneumologie (DGP) unter Mitarbeit von Experten der Deutschen Gesellschaft f&#252;r An&#228;sthesiologie und Intensivmedizin (DGAI) &#8211; PEG Emfehlungen. Chemother J. 2003;12(2):33-44.</RefTotal> </Reference> <Reference refNo="39"> <RefAuthor>Webb BJ</RefAuthor> <RefAuthor>Dascomb K</RefAuthor> <RefAuthor>Stenehjem E</RefAuthor> <RefAuthor>Vikram HR</RefAuthor> <RefAuthor>Agrwal N</RefAuthor> <RefAuthor>Sakata K</RefAuthor> <RefAuthor>Williams K</RefAuthor> <RefAuthor>Bockorny B</RefAuthor> <RefAuthor>Bagavathy K</RefAuthor> <RefAuthor>Mirza S</RefAuthor> <RefAuthor>Metersky M</RefAuthor> <RefAuthor>Dean NC</RefAuthor> <RefTitle>Derivation and Multicenter Validation of the Drug Resistance in Pneumonia Clinical Prediction Score</RefTitle> <RefYear>2016</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2652-63</RefPage> <RefTotal>Webb BJ, Dascomb K, Stenehjem E, Vikram HR, Agrwal N, Sakata K, Williams K, Bockorny B, Bagavathy K, Mirza S, Metersky M, Dean NC. Derivation and Multicenter Validation of the Drug Resistance in Pneumonia Clinical Prediction Score. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2652-63. DOI: 10.1128&#47;AAC.03071-15</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1128&#47;AAC.03071-15</RefLink> </Reference> <Reference refNo="41"> <RefAuthor>Infekt-Liga</RefAuthor> <RefTitle></RefTitle> <RefYear></RefYear> <RefBookTitle>Pneumonien</RefBookTitle> <RefPage></RefPage> <RefTotal>Infekt-Liga. Pneumonien. &#91;cited 2017-8-31&#93;. Available from: http:&#47;&#47;www.infektliga.de&#47;empfehlungen&#47;atemwegsinfektionen&#47;pneumonien&#47;</RefTotal> <RefLink>http:&#47;&#47;www.infektliga.de&#47;empfehlungen&#47;atemwegsinfektionen&#47;pneumonien&#47;</RefLink> </Reference> <Reference refNo="42"> <RefAuthor>Shorr AF</RefAuthor> <RefAuthor>Zilberberg MD</RefAuthor> <RefAuthor>Reichley R</RefAuthor> <RefAuthor>Kan J</RefAuthor> <RefAuthor>Hoban A</RefAuthor> <RefAuthor>Hoffman J</RefAuthor> <RefAuthor>Micek ST</RefAuthor> <RefAuthor>Kollef MH</RefAuthor> <RefTitle>Validation of a clinical score for assessing the risk of resistant pathogens in patients with pneumonia presenting to the emergency department</RefTitle> <RefYear>2012</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>193-8</RefPage> <RefTotal>Shorr AF, Zilberberg MD, Reichley R, Kan J, Hoban A, Hoffman J, Micek ST, Kollef MH. Validation of a clinical score for assessing the risk of resistant pathogens in patients with pneumonia presenting to the emergency department. Clin Infect Dis. 2012 Jan;54(2):193-8. DOI: 10.1093&#47;cid&#47;cir813</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;cid&#47;cir813</RefLink> </Reference> <Reference refNo="43"> <RefAuthor>Jordana-Lluch E</RefAuthor> <RefAuthor>Gim&#233;nez M</RefAuthor> <RefAuthor>Quesada MD</RefAuthor> <RefAuthor>Rivaya B</RefAuthor> <RefAuthor>Marc&#243; C</RefAuthor> <RefAuthor>Dom&#237;nguez MJ</RefAuthor> <RefAuthor>Arm&#233;star F</RefAuthor> <RefAuthor>Martr&#243; E</RefAuthor> <RefAuthor>Ausina V</RefAuthor> <RefTitle>Evaluation of the Broad-Range PCR&#47;ESI-MS Technology in Blood Specimens for the Molecular Diagnosis of Bloodstream Infections</RefTitle> <RefYear>2015</RefYear> <RefJournal>PLoS ONE</RefJournal> <RefPage>e0140865</RefPage> <RefTotal>Jordana-Lluch E, Gim&#233;nez M, Quesada MD, Rivaya B, Marc&#243; C, Dom&#237;nguez MJ, Arm&#233;star F, Martr&#243; E, Ausina V. Evaluation of the Broad-Range PCR&#47;ESI-MS Technology in Blood Specimens for the Molecular Diagnosis of Bloodstream Infections. PLoS ONE. 2015;10(10):e0140865. DOI: 10.1371&#47;journal.pone.0140865</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1371&#47;journal.pone.0140865</RefLink> </Reference> <Reference refNo="44"> <RefAuthor>Vincent JL</RefAuthor> <RefAuthor>Brealey D</RefAuthor> <RefAuthor>Libert N</RefAuthor> <RefAuthor>Abidi NE</RefAuthor> <RefAuthor>O&#8217;Dwyer M</RefAuthor> <RefAuthor>Zacharowski K</RefAuthor> <RefAuthor>Mikaszewska-Sokolewicz M</RefAuthor> <RefAuthor>Schrenzel J</RefAuthor> <RefAuthor>Simon F</RefAuthor> <RefAuthor>Wilks M</RefAuthor> <RefAuthor>Picard-Maureau M</RefAuthor> <RefAuthor>Chalfin DB</RefAuthor> <RefAuthor>Ecker DJ</RefAuthor> <RefAuthor>Sampath R</RefAuthor> <RefAuthor>Singer M</RefAuthor> <RefAuthor> Rapid Diagnosis of Infections in the Critically Ill Team</RefAuthor> <RefTitle>Rapid Diagnosis of Infection in the Critically Ill, a Multicenter Study of Molecular Detection in Bloodstream Infections, Pneumonia, and Sterile Site Infections</RefTitle> <RefYear>2015</RefYear> <RefJournal>Crit Care Med</RefJournal> <RefPage>2283-91</RefPage> <RefTotal>Vincent JL, Brealey D, Libert N, Abidi NE, O&#8217;Dwyer M, Zacharowski K, Mikaszewska-Sokolewicz M, Schrenzel J, Simon F, Wilks M, Picard-Maureau M, Chalfin DB, Ecker DJ, Sampath R, Singer M; Rapid Diagnosis of Infections in the Critically Ill Team. Rapid Diagnosis of Infection in the Critically Ill, a Multicenter Study of Molecular Detection in Bloodstream Infections, Pneumonia, and Sterile Site Infections. Crit Care Med. 2015 Nov;43(11):2283-91. DOI: 10.1097&#47;CCM.0000000000001249</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1097&#47;CCM.0000000000001249</RefLink> </Reference> <Reference refNo="45"> <RefAuthor>Bacconi A</RefAuthor> <RefAuthor>Richmond GS</RefAuthor> <RefAuthor>Baroldi MA</RefAuthor> <RefAuthor>Laffler TG</RefAuthor> <RefAuthor>Blyn LB</RefAuthor> <RefAuthor>Carolan HE</RefAuthor> <RefAuthor>Frinder MR</RefAuthor> <RefAuthor>Toleno DM</RefAuthor> <RefAuthor>Metzgar D</RefAuthor> <RefAuthor>Gutierrez JR</RefAuthor> <RefAuthor>Massire C</RefAuthor> <RefAuthor>Rounds M</RefAuthor> <RefAuthor>Kennel NJ</RefAuthor> <RefAuthor>Rothman RE</RefAuthor> <RefAuthor>Peterson S</RefAuthor> <RefAuthor>Carroll KC</RefAuthor> <RefAuthor>Wakefield T</RefAuthor> <RefAuthor>Ecker DJ</RefAuthor> <RefAuthor>Sampath R</RefAuthor> <RefTitle>Improved sensitivity for molecular detection of bacterial and Candida infections in blood</RefTitle> <RefYear>2014</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>3164-74</RefPage> <RefTotal>Bacconi A, Richmond GS, Baroldi MA, Laffler TG, Blyn LB, Carolan HE, Frinder MR, Toleno DM, Metzgar D, Gutierrez JR, Massire C, Rounds M, Kennel NJ, Rothman RE, Peterson S, Carroll KC, Wakefield T, Ecker DJ, Sampath R. Improved sensitivity for molecular detection of bacterial and Candida infections in blood. J Clin Microbiol. 2014 Sep;52(9):3164-74. DOI: 10.1128&#47;JCM.00801-14</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1128&#47;JCM.00801-14</RefLink> </Reference> <Reference refNo="46"> <RefAuthor>Sango A</RefAuthor> <RefAuthor>McCarter YS</RefAuthor> <RefAuthor>Johnson D</RefAuthor> <RefAuthor>Ferreira J</RefAuthor> <RefAuthor>Guzman N</RefAuthor> <RefAuthor>Jankowski CA</RefAuthor> <RefTitle>Stewardship approach for optimizing antimicrobial therapy through use of a rapid microarray assay on blood cultures positive for Enterococcus species</RefTitle> <RefYear>2013</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>4008-11</RefPage> <RefTotal>Sango A, McCarter YS, Johnson D, Ferreira J, Guzman N, Jankowski CA. Stewardship approach for optimizing antimicrobial therapy through use of a rapid microarray assay on blood cultures positive for Enterococcus species. J Clin Microbiol. 2013 Dec;51(12):4008-11. DOI: 10.1128&#47;JCM.01951-13</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1128&#47;JCM.01951-13</RefLink> </Reference> <Reference refNo="47"> <RefAuthor>Nguyen DT</RefAuthor> <RefAuthor>Yeh E</RefAuthor> <RefAuthor>Perry S</RefAuthor> <RefAuthor>Luo RF</RefAuthor> <RefAuthor>Pinsky BA</RefAuthor> <RefAuthor>Lee BP</RefAuthor> <RefAuthor>Sisodiya D</RefAuthor> <RefAuthor>Baron EJ</RefAuthor> <RefAuthor>Banaei N</RefAuthor> <RefTitle>Real-time PCR testing for mecA reduces vancomycin usage and length of hospitalization for patients infected with methicillin-sensitive staphylococci</RefTitle> <RefYear>2010</RefYear> <RefJournal>J Clin Microbiol</RefJournal> <RefPage>785-90</RefPage> <RefTotal>Nguyen DT, Yeh E, Perry S, Luo RF, Pinsky BA, Lee BP, Sisodiya D, Baron EJ, Banaei N. Real-time PCR testing for mecA reduces vancomycin usage and length of hospitalization for patients infected with methicillin-sensitive staphylococci. J Clin Microbiol. 2010 Mar;48(3):785-90. DOI: 10.1128&#47;JCM.02150-09</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1128&#47;JCM.02150-09</RefLink> </Reference> <Reference refNo="48"> <RefAuthor>Weber A</RefAuthor> <RefAuthor>Schneider C</RefAuthor> <RefAuthor>Grill E</RefAuthor> <RefAuthor>Strobl R</RefAuthor> <RefAuthor>Vetter-Kerkhoff C</RefAuthor> <RefAuthor>Jauch KW</RefAuthor> <RefTitle>Interventionen eines Apothekers auf chirurgischen Normalstationen &#8211; Auswirkungen auf die Antibiotikatherapie</RefTitle> <RefYear>2011</RefYear> <RefJournal>Zentralbl Chir</RefJournal> <RefPage>66-73</RefPage> <RefTotal>Weber A, Schneider C, Grill E, Strobl R, Vetter-Kerkhoff C, Jauch KW. Interventionen eines Apothekers auf chirurgischen Normalstationen &#8211; Auswirkungen auf die Antibiotikatherapie &#91;Interventions by clinical pharmacists on surgical wards &#8211; impact on antibiotic therapy&#93;. Zentralbl Chir. 2011 Feb;136(1):66-73. DOI: 10.1055&#47;s-0030-1247469</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1055&#47;s-0030-1247469</RefLink> </Reference> <Reference refNo="49"> <RefAuthor>Geerlings SE</RefAuthor> <RefAuthor>Hulscher M</RefAuthor> <RefAuthor>Prins JM</RefAuthor> <RefTitle>Goed antibioticagebruik verkort de opnameduur</RefTitle> <RefYear>2014</RefYear> <RefJournal>Ned Tijdschr Geneeskd</RefJournal> <RefPage>A7288</RefPage> <RefTotal>Geerlings SE, Hulscher M, Prins JM. Goed antibioticagebruik verkort de opnameduur. Ned Tijdschr Geneeskd. 2014;158:A7288.</RefTotal> </Reference> <Reference refNo="50"> <RefAuthor>Cisneros JM</RefAuthor> <RefAuthor>Neth O</RefAuthor> <RefAuthor>Gil-Navarro MV</RefAuthor> <RefAuthor>Lepe JA</RefAuthor> <RefAuthor>Jim&#233;nez-Parrilla F</RefAuthor> <RefAuthor>Cordero E</RefAuthor> <RefAuthor>Rodr&#237;guez-Hern&#225;ndez MJ</RefAuthor> <RefAuthor>Amaya-Villar R</RefAuthor> <RefAuthor>Cano J</RefAuthor> <RefAuthor>Guti&#233;rrez-Pizarraya A</RefAuthor> <RefAuthor>Garc&#237;a-Cabrera E</RefAuthor> <RefAuthor>Molina J</RefAuthor> <RefAuthor> PRIOAM team</RefAuthor> <RefTitle>Global impact of an educational antimicrobial stewardship programme on prescribing practice in a tertiary hospital centre</RefTitle> <RefYear>2014</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>82-8</RefPage> <RefTotal>Cisneros JM, Neth O, Gil-Navarro MV, Lepe JA, Jim&#233;nez-Parrilla F, Cordero E, Rodr&#237;guez-Hern&#225;ndez MJ, Amaya-Villar R, Cano J, Guti&#233;rrez-Pizarraya A, Garc&#237;a-Cabrera E, Molina J; PRIOAM team. Global impact of an educational antimicrobial stewardship programme on prescribing practice in a tertiary hospital centre. Clin Microbiol Infect. 2014 Jan;20(1):82-8. DOI: 10.1111&#47;1469-0691.12191</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1111&#47;1469-0691.12191</RefLink> </Reference> <Reference refNo="51"> <RefAuthor>Davey P</RefAuthor> <RefAuthor>Brown E</RefAuthor> <RefAuthor>Charani E</RefAuthor> <RefAuthor>Fenelon L</RefAuthor> <RefAuthor>Gould IM</RefAuthor> <RefAuthor>Holmes A</RefAuthor> <RefAuthor>Ramsay CR</RefAuthor> <RefAuthor>Wiffen PJ</RefAuthor> <RefAuthor>Wilcox M</RefAuthor> <RefTitle>Interventions to improve antibiotic prescribing practices for hospital inpatients</RefTitle> <RefYear>2013</RefYear> <RefJournal>Cochrane Database Syst Rev</RefJournal> <RefPage>CD003543</RefPage> <RefTotal>Davey P, Brown E, Charani E, Fenelon L, Gould IM, Holmes A, Ramsay CR, Wiffen PJ, Wilcox M. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2013 Apr 30;(4):CD003543. DOI: 10.1002&#47;14651858.CD003543.pub3</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1002&#47;14651858.CD003543.pub3</RefLink> </Reference> <Reference refNo="52"> <RefAuthor>Kern WV</RefAuthor> <RefTitle>Antibiotic Stewardship &#8211; Strategien zur Sicherung eines intelligenten und rationalen Antibiotikaeinsatzes</RefTitle> <RefYear>2014</RefYear> <RefJournal>Drug Res (Stuttg)</RefJournal> <RefPage>S5</RefPage> <RefTotal>Kern WV. Antibiotic Stewardship &#8211; Strategien zur Sicherung eines intelligenten und rationalen Antibiotikaeinsatzes &#91;Antibiotic stewardship &#8211; strategies for ensuring an intelligent and rational use of antibiotics&#93;. Drug Res (Stuttg). 2014 Nov;64 Suppl 1:S5. DOI: 10.1055&#47;s-0033-1358027</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1055&#47;s-0033-1358027</RefLink> </Reference> <Reference refNo="53"> <RefAuthor>Mertz D</RefAuthor> <RefAuthor>Koller M</RefAuthor> <RefAuthor>Haller P</RefAuthor> <RefAuthor>Lampert ML</RefAuthor> <RefAuthor>Plagge H</RefAuthor> <RefAuthor>Hug B</RefAuthor> <RefAuthor>Koch G</RefAuthor> <RefAuthor>Battegay M</RefAuthor> <RefAuthor>Fl&#252;ckiger U</RefAuthor> <RefAuthor>Bassetti S</RefAuthor> <RefTitle>Outcomes of early switching from intravenous to oral antibiotics on medical wards</RefTitle> <RefYear>2009</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>188-99</RefPage> <RefTotal>Mertz D, Koller M, Haller P, Lampert ML, Plagge H, Hug B, Koch G, Battegay M, Fl&#252;ckiger U, Bassetti S. Outcomes of early switching from intravenous to oral antibiotics on medical wards. J Antimicrob Chemother. 2009 Jul;64(1):188-99. DOI: 10.1093&#47;jac&#47;dkp131</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;jac&#47;dkp131</RefLink> </Reference> <Reference refNo="54"> <RefAuthor>Nathwani D</RefAuthor> <RefAuthor>Eckmann C</RefAuthor> <RefAuthor>Lawson W</RefAuthor> <RefAuthor>Stephens JM</RefAuthor> <RefAuthor>Macahilig C</RefAuthor> <RefAuthor>Solem CT</RefAuthor> <RefAuthor>Simoneau D</RefAuthor> <RefAuthor>Chambers R</RefAuthor> <RefAuthor>Li JZ</RefAuthor> <RefAuthor>Haider S</RefAuthor> <RefTitle>Pan-European early switch&#47;early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections</RefTitle> <RefYear>2014</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>993-1000</RefPage> <RefTotal>Nathwani D, Eckmann C, Lawson W, Stephens JM, Macahilig C, Solem CT, Simoneau D, Chambers R, Li JZ, Haider S. Pan-European early switch&#47;early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections. Clin Microbiol Infect. 2014 Oct;20(10):993-1000. DOI: 10.1111&#47;1469-0691.12632</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1111&#47;1469-0691.12632</RefLink> </Reference> <Reference refNo="55"> <RefAuthor>Gray A</RefAuthor> <RefAuthor>Dryden M</RefAuthor> <RefAuthor>Charos A</RefAuthor> <RefTitle>Antibiotic management and early discharge from hospital: an economic analysis</RefTitle> <RefYear>2012</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>2297-302</RefPage> <RefTotal>Gray A, Dryden M, Charos A. Antibiotic management and early discharge from hospital: an economic analysis. J Antimicrob Chemother. 2012 Sep;67(9):2297-302. DOI: 10.1093&#47;jac&#47;dks194</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;jac&#47;dks194</RefLink> </Reference> <Reference refNo="56"> <RefAuthor>Berild D</RefAuthor> <RefAuthor>Mohseni A</RefAuthor> <RefAuthor>Diep LM</RefAuthor> <RefAuthor>Jensenius M</RefAuthor> <RefAuthor>Ringertz SH</RefAuthor> <RefTitle>Adjustment of antibiotic treatment according to the results of blood cultures leads to decreased antibiotic use and costs</RefTitle> <RefYear>2006</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>326-30</RefPage> <RefTotal>Berild D, Mohseni A, Diep LM, Jensenius M, Ringertz SH. Adjustment of antibiotic treatment according to the results of blood cultures leads to decreased antibiotic use and costs. J Antimicrob Chemother. 2006 Feb;57(2):326-30. DOI: 10.1093&#47;jac&#47;dki463</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1093&#47;jac&#47;dki463</RefLink> </Reference> <Reference refNo="57"> <RefAuthor>Jelassi ML</RefAuthor> <RefAuthor>Benlmouden A</RefAuthor> <RefAuthor>Lefeuvre S</RefAuthor> <RefAuthor>Mainardi J</RefAuthor> <RefAuthor>Billaud EM</RefAuthor> <RefTitle>Niveau de preuve pour le suivi th&#233;rapeutique pharmacologique de la vancomycine</RefTitle> <RefYear>2011</RefYear> <RefJournal>Th&#233;rapie</RefJournal> <RefPage>29&#8211;37</RefPage> <RefTotal>Jelassi ML, Benlmouden A, Lefeuvre S, Mainardi J, Billaud EM. Niveau de preuve pour le suivi th&#233;rapeutique pharmacologique de la vancomycine. Th&#233;rapie. 2011;66(1):29&#8211;37. DOI: 10.2515&#47;therapie&#47;2011005</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.2515&#47;therapie&#47;2011005</RefLink> </Reference> <Reference refNo="58"> <RefAuthor>Fern&#225;ndez de Gatta MD</RefAuthor> <RefAuthor>Calvo MV</RefAuthor> <RefAuthor>Hern&#225;ndez JM</RefAuthor> <RefAuthor>Caballero D</RefAuthor> <RefAuthor>San Miguel JF</RefAuthor> <RefAuthor>Dom&#237;nguez-Gil A</RefAuthor> <RefTitle>Cost-effectiveness analysis of serum vancomycin concentration monitoring in patients with hematologic malignancies</RefTitle> <RefYear>1996</RefYear> <RefJournal>Clin Pharmacol Ther</RefJournal> <RefPage>332-40</RefPage> <RefTotal>Fern&#225;ndez de Gatta MD, Calvo MV, Hern&#225;ndez JM, Caballero D, San Miguel JF, Dom&#237;nguez-Gil A. Cost-effectiveness analysis of serum vancomycin concentration monitoring in patients with hematologic malignancies. Clin Pharmacol Ther. 1996 Sep;60(3):332-40.</RefTotal> </Reference> <Reference refNo="59"> <RefAuthor>W&#246;rmann A</RefAuthor> <RefTitle></RefTitle> <RefYear>2015</RefYear> <RefBookTitle>Pharmako&#246;konomische &#220;berlegungen zur kontinuierlichen Infusion von &#223;-Lactam Antibiotika unter Serumspiegelkontrolle am Beispiel von Meropenem und Piperacillin&#47;Tazobactam: Masterarbeit zur Erlangung des akademischen Grades Master of Science</RefBookTitle> <RefPage></RefPage> <RefTotal>W&#246;rmann A. Pharmako&#246;konomische &#220;berlegungen zur kontinuierlichen Infusion von &#223;-Lactam Antibiotika unter Serumspiegelkontrolle am Beispiel von Meropenem und Piperacillin&#47;Tazobactam: Masterarbeit zur Erlangung des akademischen Grades Master of Science. Dresden: Dresden International University;2015.</RefTotal> </Reference> <Reference refNo="60"> <RefAuthor>Tice AD</RefAuthor> <RefAuthor>Turpin RS</RefAuthor> <RefAuthor>Hoey CT</RefAuthor> <RefAuthor>Lipsky BA</RefAuthor> <RefAuthor>Wu J</RefAuthor> <RefAuthor>Abramson MA</RefAuthor> <RefTitle>Comparative costs of ertapenem and piperacillin-tazobactam in the treatment of diabetic foot infections</RefTitle> <RefYear>2007</RefYear> <RefJournal>Am J Health Syst Pharm</RefJournal> <RefPage>1080-6</RefPage> <RefTotal>Tice AD, Turpin RS, Hoey CT, Lipsky BA, Wu J, Abramson MA. Comparative costs of ertapenem and piperacillin-tazobactam in the treatment of diabetic foot infections. Am J Health Syst Pharm. 2007 May;64(10):1080-6.</RefTotal> </Reference> <Reference refNo="61"> <RefAuthor>van Zanten AR</RefAuthor> <RefAuthor>Engelfriet PM</RefAuthor> <RefAuthor>van Dillen K</RefAuthor> <RefAuthor>van Veen M</RefAuthor> <RefAuthor>Nuijten MJ</RefAuthor> <RefAuthor>Polderman KH</RefAuthor> <RefTitle>Importance of nondrug costs of intravenous antibiotic therapy</RefTitle> <RefYear>2003</RefYear> <RefJournal>Crit Care</RefJournal> <RefPage>R184-90</RefPage> <RefTotal>van Zanten AR, Engelfriet PM, van Dillen K, van Veen M, Nuijten MJ, Polderman KH. Importance of nondrug costs of intravenous antibiotic therapy. Crit Care. 2003 Dec;7(6):R184-90. DOI: 10.1186&#47;cc2388</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1186&#47;cc2388</RefLink> </Reference> <Reference refNo="62"> <RefAuthor>Cheung KC</RefAuthor> <RefAuthor>van Rhijn A</RefAuthor> <RefAuthor>Cousins D</RefAuthor> <RefAuthor>De Smet P</RefAuthor> <RefTitle>Improving European cooperation on medication errors</RefTitle> <RefYear>2014</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>1209-10</RefPage> <RefTotal>Cheung KC, van Rhijn A, Cousins D, De Smet P. Improving European cooperation on medication errors. Lancet. 2014 Apr 5;383(9924):1209-10. DOI: 10.1016&#47;S0140-6736(14)60603-6</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1016&#47;S0140-6736(14)60603-6</RefLink> </Reference> <Reference refNo="63"> <RefAuthor>Center for Disease Dynamics</RefAuthor> <RefAuthor>Economics &#38; Policy</RefAuthor> <RefTitle></RefTitle> <RefYear>2015</RefYear> <RefBookTitle>The State of the World&#8217;s Antibiotics 2015</RefBookTitle> <RefPage></RefPage> <RefTotal>Center for Disease Dynamics, Economics &#38; Policy, editor. The State of the World&#8217;s Antibiotics 2015. Washington: CDDEP; 2015. Available from: https:&#47;&#47;www.cddep.org&#47;wp-content&#47;uploads&#47;2017&#47;06&#47;swa&#95;edits&#95;9.16.pdf</RefTotal> <RefLink>https:&#47;&#47;www.cddep.org&#47;wp-content&#47;uploads&#47;2017&#47;06&#47;swa&#95;edits&#95;9.16.pdf</RefLink> </Reference> <Reference refNo="64"> <RefAuthor>World Health Organization</RefAuthor> <RefTitle></RefTitle> <RefYear>2014</RefYear> <RefBookTitle>Antimicrobial Resistance: Global Report on Surveillance: Global Report on Surveillance</RefBookTitle> <RefPage></RefPage> <RefTotal>World Health Organization. Antimicrobial Resistance: Global Report on Surveillance: Global Report on Surveillance. Geneva: World Health Organization; 2014. Available from: http:&#47;&#47;apps.who.int&#47;iris&#47;bitstream&#47;10665&#47;112642&#47;1&#47;9789241564748&#95;eng.pdf&#63;ua&#61;1</RefTotal> <RefLink>http:&#47;&#47;apps.who.int&#47;iris&#47;bitstream&#47;10665&#47;112642&#47;1&#47;9789241564748&#95;eng.pdf&#63;ua&#61;1</RefLink> </Reference> <Reference refNo="65"> <RefAuthor>Robert Koch Institut</RefAuthor> <RefTitle></RefTitle> <RefYear>2014</RefYear> <RefBookTitle>Ergebnisse der Studie &#8222;Gesundheit in Deutschland aktuell 2012&#8220;. Kapitel 2: Gesundheitstrends bei Erwachsenen in Deutschland zwischen 2003 und 2012. (Beitr&#228;ge zur Gesundheitsberichterstattung des Bundes)</RefBookTitle> <RefPage></RefPage> <RefTotal>Robert Koch Institut. Daten und Fakten: Ergebnisse der Studie &#8222;Gesundheit in Deutschland aktuell 2012&#8220;. Berlin: Robert Koch-Institut; 2014. Kapitel 2: Gesundheitstrends bei Erwachsenen in Deutschland zwischen 2003 und 2012. (Beitr&#228;ge zur Gesundheitsberichterstattung des Bundes). Available from: https:&#47;&#47;www.rki.de&#47;DE&#47;Content&#47;Gesundheitsmonitoring&#47;Studien&#47;Geda&#47;kapitel&#95;gesundheitstrends.pdf&#63;&#95;&#95;blob&#61;publicationFile</RefTotal> <RefLink>https:&#47;&#47;www.rki.de&#47;DE&#47;Content&#47;Gesundheitsmonitoring&#47;Studien&#47;Geda&#47;kapitel&#95;gesundheitstrends.pdf&#63;&#95;&#95;blob&#61;publicationFile</RefLink> </Reference> <Reference refNo="66"> <RefAuthor>Ott E</RefAuthor> <RefAuthor>Bange FC</RefAuthor> <RefAuthor>Reichardt C</RefAuthor> <RefAuthor>Graf K</RefAuthor> <RefAuthor>Eckstein M</RefAuthor> <RefAuthor>Schwab F</RefAuthor> <RefAuthor>Chaberny IF</RefAuthor> <RefTitle>Costs of nosocomial pneumonia caused by meticillin-resistant Staphylococcus aureus</RefTitle> <RefYear>2010</RefYear> <RefJournal>J Hosp Infect</RefJournal> <RefPage>300-3</RefPage> <RefTotal>Ott E, Bange FC, Reichardt C, Graf K, Eckstein M, Schwab F, Chaberny IF. Costs of nosocomial pneumonia caused by meticillin-resistant Staphylococcus aureus. J Hosp Infect. 2010 Dec;76(4):300-3. DOI: 10.1016&#47;j.jhin.2010.07.007</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1016&#47;j.jhin.2010.07.007</RefLink> </Reference> <Reference refNo="67"> <RefAuthor>Aldeyab MA</RefAuthor> <RefAuthor>Kearney MP</RefAuthor> <RefAuthor>McElnay JC</RefAuthor> <RefAuthor>Magee FA</RefAuthor> <RefAuthor>Conlon G</RefAuthor> <RefAuthor>Gill D</RefAuthor> <RefAuthor>Davey P</RefAuthor> <RefAuthor>Muller A</RefAuthor> <RefAuthor>Goossens H</RefAuthor> <RefAuthor>Scott MG</RefAuthor> <RefAuthor> ESAC Hospital Care Subproject Group</RefAuthor> <RefTitle>A point prevalence survey of antibiotic prescriptions: benchmarking and patterns of use</RefTitle> <RefYear>2011</RefYear> <RefJournal>Br J Clin Pharmacol</RefJournal> <RefPage>293-6</RefPage> <RefTotal>Aldeyab MA, Kearney MP, McElnay JC, Magee FA, Conlon G, Gill D, Davey P, Muller A, Goossens H, Scott MG; ESAC Hospital Care Subproject Group. A point prevalence survey of antibiotic prescriptions: benchmarking and patterns of use. Br J Clin Pharmacol. 2011 Feb;71(2):293-6. DOI: 10.1111&#47;j.1365-2125.2010.03840.x</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1111&#47;j.1365-2125.2010.03840.x</RefLink> </Reference> <Reference refNo="68"> <RefAuthor>Resch A</RefAuthor> <RefAuthor>Wilke M</RefAuthor> <RefAuthor>Fink C</RefAuthor> <RefTitle>The cost of resistance: incremental cost of methicillin-resistant Staphylococcus aureus (MRSA) in German hospitals</RefTitle> <RefYear>2009</RefYear> <RefJournal>Eur J Health Econ</RefJournal> <RefPage>287-97</RefPage> <RefTotal>Resch A, Wilke M, Fink C. The cost of resistance: incremental cost of methicillin-resistant Staphylococcus aureus (MRSA) in German hospitals. Eur J Health Econ. 2009 Jul;10(3):287-97. DOI: 10.1007&#47;s10198-008-0132-3</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1007&#47;s10198-008-0132-3</RefLink> </Reference> <Reference refNo="69"> <RefAuthor>Engemann JJ</RefAuthor> <RefAuthor>Carmeli Y</RefAuthor> <RefAuthor>Cosgrove SE</RefAuthor> <RefAuthor>Fowler VG</RefAuthor> <RefAuthor>Bronstein MZ</RefAuthor> <RefAuthor>Trivette SL</RefAuthor> <RefAuthor>Briggs JP</RefAuthor> <RefAuthor>Sexton DJ</RefAuthor> <RefAuthor>Kaye KS</RefAuthor> <RefTitle>Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection</RefTitle> <RefYear>2003</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>592-8</RefPage> <RefTotal>Engemann JJ, Carmeli Y, Cosgrove SE, Fowler VG, Bronstein MZ, Trivette SL, Briggs JP, Sexton DJ, Kaye KS. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis. 2003 Mar;36(5):592-8. DOI: 10.1086&#47;367653</RefTotal> <RefLink>https:&#47;&#47;doi.org&#47;10.1086&#47;367653</RefLink> </Reference> <Reference refNo="70"> <RefAuthor>O&#8217;Neill J</RefAuthor> <RefTitle></RefTitle> <RefYear>2014</RefYear> <RefBookTitle>Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations: The Review on Antimicrobial Resistance</RefBookTitle> <RefPage></RefPage> <RefTotal>O&#8217;Neill J. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations: The Review on Antimicrobial Resistance. London: HM Government; 2014.</RefTotal> </Reference> </References> <Media> <Tables> <Table format="png"> <MediaNo>1</MediaNo> <MediaID language="de">1de</MediaID> <MediaID language="en">1en</MediaID> <Caption language="de"><Pgraph><Mark1>Tabelle 1: &#220;bersicht &#246;konomisch empfehlenswerter Strategien</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 1: Overview of economically recommended strategies</Mark1></Pgraph></Caption> </Table> <NoOfTables>1</NoOfTables> </Tables> <Figures> <NoOfPictures>0</NoOfPictures> </Figures> <InlineFigures> <NoOfPictures>0</NoOfPictures> </InlineFigures> <Attachments> <NoOfAttachments>0</NoOfAttachments> </Attachments> </Media> </OrigData> </GmsArticle>