Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Pharmakokinetik und Pharmakodynamik

id000061 10.3205/id000061 urn:nbn:de:0183-id0000618 Leitlinie Guideline Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Pharmakokinetik und Pharmakodynamik Calculated initial parenteral treatment of bacterial infections: Pharmacokinetics and pharmacodynamics Derendorf Derendorf Hartmut H Prof. Dr.

Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive, P3-27, Gainesville, FL 32610-0494, USADepartment of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, USA

hartmut@ufl.edu author Heinrichs Heinrichs Tobias T

Bayer AG, Klinische Pharmazie, Leverkusen, DeutschlandBayer AG, Klinische Pharmazie, Leverkusen, Deutschland

Bayer AG, Klinische Pharmazie, Leverkusen, GermanyBayer AG, Klinische Pharmazie, Leverkusen, Germany

author Reimers Reimers Tobias T

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, USADepartment of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, USA

author Lebert Lebert Cordula C

Apotheke, Klinikum Nürnberg, DeutschlandApotheke, Klinikum Nürnberg, Deutschland

Apotheke, Klinikum Nürnberg, Nuremberg, GermanyApotheke, Klinikum Nürnberg, Nuremberg, Germany

author Brinkmann Brinkmann Alexander A

Klinik für Anästhesie, operative Intensivmedizin und spezielle Schmerztherapie, Klinikum Heidenheim, DeutschlandKlinik für Anästhesie, operative Intensivmedizin und spezielle Schmerztherapie, Klinikum Heidenheim, Deutschland

Klinik für Anästhesie, operative Intensivmedizin und spezielle Schmerztherapie, Klinikum Heidenheim, GermanyKlinik für Anästhesie, operative Intensivmedizin und spezielle Schmerztherapie, Klinikum Heidenheim, 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 17 Dies ist das dritte 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 bespricht die pharmakokinetischen und pharmakodynamischen Eigenschaften der am häufigsten eingesetzten Antiinfektiva. This is the third 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. The chapter features the pharmacokinetic and pharmacodynamics properties of the most frequently used antiinfective agents. PharmakologieNeben den antimikrobiellen Eigenschaften (Pharmakodynamik) einer Substanz spielen die pharmakokinetischen Eigenschaften, also das Verhalten im Organismus, eine entscheidende Rolle. Letztlich geht es um die Frage, ob die Konzentrationen am Wirkort ausreichend sind, um die Erreger zu hemmen, abzutöten und möglicherweise die Entwicklung von resistenten Erregern zu vermeiden. Unerwünschte Arzneimittelwirkungen und Interaktionen sollten minimiert werden.Wenn pharmakokinetische Parameter, oder im einfachsten Fall Plasma- und Gewebskonzentrationen, mit den antimikrobiellen Eigenschaften in vitro oder in vivo zum Zweck der Wirksamkeitsvorhersage in Verbindung gebracht werden, spricht man von PK/PD (Pharmakokinetik/Pharmakodynamik). PharmacologyIn addition to the antimicrobial properties (pharmacodynamics) of a substance, the pharmacokinetic properties, i.e. the behavior in an organism, play a decisive role. Ultimately the question is whether the concentrations at the site of action are sufficient to inhibit the pathogens, kill them and possibly prevent the development of resistant pathogens. Adverse drug reactions and interactions should be minimized.For the purpose of predicting efficacy, one speaks of PK/PD (pharmacokinetics/pharmacodynamics) when pharmacokinetic parameters or, in the simplest case, plasma and tissue concentrations are associated with the antimicrobial properties in vitro or in vivo. PharmakokinetikPharmakokinetische Eigenschaften von Arzneistoffen werden von ihren physikochemischen Charakteristika bestimmt. Die Säure- oder Basenstärke einer Substanz, ihre Lipophilie oder Hydrophilie bestimmen, wie sich die Substanz unter den physiologischen Bedingungen des Organismus verhält. Beta-Lactam-Antibiotika und Aminoglykoside z.B. sind schlecht membrangängig und befinden sich deshalb hauptsächlich im Extrazellularraum. Eine Übersicht pharmakokinetischer Parameter einzelner Substanzgruppen zeigt Tabelle 1 .Ein wichtiger pharmakokinetischer Parameter, der die Verteilung des Arzneistoffs im Körper beschreibt, ist das Verteilungsvolumen. Lipophile Substanzen, welche gut Membranen passieren können, werden passiv intrazellulär aufgenommen. Ihr Verteilungsvolumen ist daher hoch; es kann bei Fluorchinolonen und Makroliden ein Vielfaches des Körpervolumens betragen. Substanzen mit großen Verteilungsvolumina besitzen geringere Plasma- und Interstitialspiegel, aber hohe intrazelluläre Konzentrationen. Wasserlösliche Substanzen hingegen penetrieren schwer durch Zellmembranen und halten sich deshalb vornehmlich in Plasma und Interstitium auf. Die meisten Erreger befinden sich im Interstitium, so dass in diesen Fällen die Konzentration dort entscheidend ist.Ein wichtiger Aspekt bei der Arzneistoffverteilung ist die Proteinbindung im Serum. Antibiotika binden abhängig von ihren physikochemischen Eigenschaften hauptsächlich an Albumin. Die konzentrationsabhängige Bindung ist reversibel. Es besteht ein dynamisches Gleichgewicht zwischen dem freien und gebundenen Anteil. Allgemein gilt, dass nur der freie, nicht an Protein gebundene Anteil eines Antibiotikums für dessen Wirkung verantwortlich ist. Wie für einige Antibiotika gezeigt, muss eine hohe Proteinbindung die Wirksamkeit einer Substanz nicht negativ beeinflussen, solange ausreichend hohe ungebundene Konzentrationen am Wirkort vorliegen. Klinische Studien, die einen negativen Einfluss der Proteinbindung zu belegen scheinen, wurden häufig mit zu geringen Gesamtdosen durchgeführt , , . Weiter spielt die Proteinbindung bei Niereners</PlainText></TextGroup>atzverfahren eine Rolle. Lediglich der freie, nicht proteingebundene Wirkstoffanteil kann über die künstlichen Membranen eines Nierenersatzverfahrens eliminiert werden.</Pgraph><Pgraph>Ähnlich wichtig ist die Bedeutung der Gewebskonzentrationen für die Vorhersage der Wirksamkeit. Gewebskonzentrationen, wie sie aus Biopsiematerial oder chirurgischen Resektaten bestimmt werden können, stellen die durchschnittlichen Konzentrationen im Gewebehomogenat dar. Sie werden weder den komplexen Vorgängen noch der heterogenen Verteilung im Gewebe gerecht. Bedeutung haben die Messungen der Gewebskonzentrationen z.B. beim Vergleich zweier Substanzen oder Substanzgruppen.</Pgraph><Pgraph>Ein großer Fortschritt konnte auf diesem Gebiet mit der Entwicklung der Mikrodialyse gemacht werden. Von Bedeutung ist die Messung von Antibiotika-Konzentrationen in Kompartimenten wie Zerebrospinalflüssigkeit, Alveolarfilm, Pleuraflüssigkeit, Peritonealflüssigkeit, Pankreas- und Prostatasekret. Krankheitsbedingte Mikrozirkulationsstörungen mit kompromittierter Gewebedurchblutung, anatomisch besonders strukturierte Zellmembranen sowie Vorhandensein von spezifischen Geweberezeptoren können Hindernisse für eine gleichmäßige Verteilung von Antibiotika darstellen und damit den Therapieerfolg beeinflussen. Tabelle 2 <ImgLink imgNo="2" imgType="table"/> zeigt die Erreichbarkeit verschiedener Kompartimente für Antibiotika. Damit spielen nicht nur die physikochemischen Eigenschaften der Antiinfektiva, sondern ebenfalls die Durchblutung der tiefen Kompartimente eine entscheidende Rolle für die tatsächliche Wirkortkonzentration <TextLink reference="4"></TextLink>, <TextLink reference="5"></TextLink>, <TextLink reference="6"></TextLink>.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Pharmacokinetics"> <MainHeadline>Pharmacokinetics</MainHeadline><Pgraph>Pharmacokinetic properties of drugs are determined by their physicochemical characteristics. The acid or base strength of a substance, its lipophilicity or hydrophilicity determine how the substance behaves under the physiological conditions of an organism. For example beta-lactam antibiotics and aminoglycosides are poor at penetrating membranes and therefore are located mainly in the extracellular space. An overview of pharmacokinetic parameters of individual substance groups is shown in Table 1 <ImgLink imgNo="1" imgType="table"/>.</Pgraph><Pgraph>An important pharmacokinetic parameter that describes the distribution of the drug in the body is the volume of distribution. Lipophilic substances, which can easily pass through membranes, are passively taken up intracellularly. Their volume of distribution is therefore high; with fluoroquinolones and macrolides it can be a multiple of the body volume. Substances with large volumes of distribution have lower plasma and interstitial levels but high intracellular concentrations. Water-soluble substances, on the other hand, penetrate cell membranes with difficulty and therefore mainly remain in the plasma and interstitium. Most pathogens are located in the interstitium, so concentration in these cases is crucial.</Pgraph><Pgraph>An important aspect of drug distribution is protein binding in serum. Depending on their physicochemical properties, antibiotics mainly bind to albumin. </Pgraph><Pgraph>Concentration-dependent binding is reversible. There is a dynamic balance between the free and the bound portion. In general, only the free, non protein-bound portion of an antibiotic is responsible for its action. As demonstrated for some antibiotics, high protein binding need not adversely affect the efficacy of a substance as long as there are sufficiently high unbound concentrations at the site of action. Clinical studies that appear to demonstrate a negative influence of protein binding were often performed with low total doses <TextLink reference="1"></TextLink>, <TextLink reference="2"></TextLink>, <TextLink reference="3"></TextLink>. Furthermore, protein binding plays a role in kidney replacement procedures. Only the free, non protein-bound active substance portion can be eliminated via the artificial membranes of a kidney replacement procedure.</Pgraph><Pgraph>Equally significant for predicting efficacy is the question of tissue concentration. Tissue concentrations, as determined from biopsy material or surgical resectates, represent average concentrations in tissue homogenate. They do not adequately represent the complex processes or the heterogeneous distribution in the tissue. The measurements of tissue concentrations are important, for example when comparing two substances or substance groups.</Pgraph><Pgraph>Big progress was made in this area with the development of microdialysis. The measurement of antibiotic concentrations in compartments such as cerebrospinal fluid, alveolar film, pleural fluid, peritoneal fluid, pancreatic and prostatic fluid is important. Disease-related microcirculatory disturbances with compromised tissue perfusion, cell membranes with special anatomic structures and the presence of specific tissue receptors can be obstacles to the even distribution of antibiotics and thus influence treatment success. Table 2 <ImgLink imgNo="2" imgType="table"/> shows the accessibility of different compartments for antibiotics. Thus, not only the physicochemical properties of the anti-infective agents but also the perfusion of the deep compartments play a crucial role in the actual site concentration <TextLink reference="4"></TextLink>, <TextLink reference="5"></TextLink>, <TextLink reference="6"></TextLink>.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Interaktion von Pharmakokinetik und Pharmakodynamik"> <MainHeadline>Interaktion von Pharmakokinetik und Pharmakodynamik</MainHeadline><Pgraph>Da noch nicht genügend Daten über die Konzentrationsprofile am Infektionsort verfügbar sind, erfolgt die pharmakokinetische Bewertung der verschiedenen Substanzen heute in der Regel mithilfe der verschiedenen Plasmakonzentrationen; die Wirkortkonzentrationen können beim schwerkranken Intensivpatienten von den Messungen im primären Kompartiment (Serum, Plasma) abweichen (besonders bei Infektionen in tiefen Kompartimenten: Lunge, Knochen, Weichteile) <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>. Je nach Wirkungsmechanismus werden für die verschiedenen Wirkstoffgruppen unterschiedliche Indizes zur Steuerung der Therapie empfohlen.</Pgraph><Pgraph>Die Unterschiede im pharmakodynamischen Profil der Antibiotika-Gruppen erklären sich auch aufgrund ihrer unterschiedlichen Wirkungsweise – konzentrationsabhängige Wirkung bei Fluorchinolonen, Aminoglykosiden, Tetracyclinen und Glycylcyclinen (Tigecyclin) und die zeitabhängige (nicht konzentrationsabhängige) Wirkung bei Beta-Lactam-Antibiotika, Lincosamiden und Makroliden (Tabelle 3 <ImgLink imgNo="3" imgType="table"/>). Bei Aminoglykosiden, Fluorchinolonen und zyklischen Lipopeptiden (Daptomycin) konnte gezeigt werden, dass das Verhältnis von Spitzenkonzentration (C<Subscript>max</Subscript>) zur minimalen Hemmkonzentration (MHK) des Erregers mit dem Therapieerfolg korreliert. Bei Beta-Lactam-Antibiotika dagegen ist es der Prozentsatz des Dosierungsintervalls, in dem die Plasmakonzentration über der MHK des Erregers liegt (t>MHK bzw. %t>MHK). Bei den Fluorchinolonen und zyklischen Lipopeptiden (Daptomycin) wird dem Quotienten aus AUC (Area under the curve, Fläche unter der Konzentrations-Zeit-Kurve) und MHK prädiktive Bedeutung zugemessen (die Fläche unter der 24 Stunden-Konzentrations-Zeit-Kurve bezogen auf die MHK: AUC<Subscript>24</Subscript>/MHK). Dies trifft auch auf die Gruppe der Glykopeptide zu. Die bisherigen Erkenntnisse zu Oxazolidinonen (Linezolid, Tedizolid) weisen darauf hin, dass sowohl die Konzentration als auch die Zeitdauer der Einwirkung relevant sind. Die Validierung dieser Modelle für den Menschen ist für einige Antibiotika-Gruppen gezeigt worden.</Pgraph><Pgraph>Insbesondere bei immunsupprimierten Patienten und bei Infektionen in schwer erreichbaren Kompartimenten (Abszesse, Osteomyelitiden, Meningitiden, nekrotisierende Infektionen, siehe auch Tabelle 2 <ImgLink imgNo="2" imgType="table"/>) ist die Berücksichtigung von PK/PD-Indizes bei der Wahl des Dosierungsregimes von entscheidender Bedeutung. Auch die pharmakokinetischen Besonderheiten der kritisch Kranken, die durch hyperdyname Kreislaufsituation, endotheliale Schäden, erhöhte kapilläre Permeabilität, Hypalbuminämie, extrakorporale Kreisläufe, intravenöse Applikation von großen Flüssigkeitsmengen oder Gabe von Vasopressoren beeinflusst werden, können zum erhöhten Verteilungsvolumen und durch Erhöhung der renalen Perfusion bei Abwesenheit von relevanten Organdysfunktionen zur Erhöhung der Clearance von hydrophilen Antibiotika und zur Abnahme ihrer Plasmakonzentration führen <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>. Bei eben dieser schwerkranken Patientenklientel sind möglicherweise neben der MHK noch andere PD-Indizes von Bedeutung. Für den therapeutischen Erfolg bei bestimmten Erregergruppen (Non-Fermenter, z.B. <Mark2>Pseudomonas aeruginos</Mark2>a) inklusive der Vermeidung von Resistenzentwicklung sind möglicherweise Konzentrationsprofile günstiger, bei denen die Wirkortkonzentrationen deutlich oberhalb der MHK (entspricht MPK, Mutanten-Präventions-Konzentration) bleiben <TextLink reference="4"></TextLink>, <TextLink reference="7"></TextLink>. </Pgraph><Pgraph>Die Daten über PK/PD-Korrelationen bieten die Möglichkeit, besonders bei Risikopopulationen (z.B. bei kritisch Kranken, bei geriatrischen Patienten, Patienten mit Organinsuffizienz, Infektionen mit multiresistenten Erregern [z.B. „Extended-Spektrum“ Beta-Lactamase (ESBL)-Bildner]) die Dosierung mithilfe des therapeutischen Drug Monitorings (TDM) individuell anzupassen <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>, <TextLink reference="10"></TextLink>.</Pgraph><Pgraph>Clearance und Verteilungsvolumen bestimmen die Halbwertszeit einer Substanz. Diese Parameter sind mitbestimmend für die Zeit, in der sich die Plasmakonzentration oberhalb der MHK befindet, sowie für die Gesamtexposition (AUC) und spielen für die Berechnung des Dosierungsintervalls eine wichtige Rolle.</Pgraph><Pgraph>Die Einschränkung der Funktion der Arzneimittel-eliminierenden Organe (vor allem der Nieren und der Leber) führt zu einer reduzierten Clearance von Antibiotika und zur Verlängerung der Halbwertszeit und kann damit ein Grund für die erhöhte Rate von unerwünschten Wirkungen sein. Die Relevanz der eingeschränkten Nieren- und Leberfunktion spielt dabei eine geringere Rolle für Antibiotika mit großer therapeutischer Breite (breitem Konzentrationsbereich zwischen den wirksamen und den toxischen Spiegeln, z.B. für Penicilline, Cephalosporine, Carbapeneme, Makrolide, Lincosamide, Fluorchinolone, Linezolid) als für Antibiotika mit enger therapeutischer Breite (z.B. Aminoglykoside, Vancomycin). Bei Intensivpatienten konnte dennoch aktuell gezeigt werden, dass erhöhte Plasmaspiegel von Beta-Lactam-Antibiotika mit einem schlechteren neurologischen Outcome verbunden sind <TextLink reference="5"></TextLink>. Bei der Auswahl der geeigneten Antibiotika spielt dann neben der mikrobiologischen Wirksamkeit das Ausmaß der renalen und extrarenalen Elimination sowie ein eventuell vorhandenes nephro- und/oder hepatotoxisches Potenzial der Antibiotika selber oder ihrer Metaboliten eine wichtige Rolle. Diese Antibiotika (potenziell nephrotoxisch: Aminoglykoside, Vancomycin, Teicoplanin, Telavancin; potenziell hepatotoxisch: Amoxicillin/Clavulansäure, Flucloxacillin, Fluorchinolone, Tetracycline, Rifampicin) sollen bei eingeschränkter Funktion des entsprechenden Organs nur bei vitaler Indikation appliziert werden. Mögliche Risiken durch eine Kumulation eventuell vorhandener toxischer Metabolite bei Patienten mit ausgeprägter Nieren- und Leberinsuffizienz sollen ebenfalls bedacht werden. Prinzipiell sollen bei eingeschränkter Nierenfunktion Antibiotika mit einer hohen extrarenalen Elimination gewählt werden, bei Leberinsuffizienz Antibiotika mit vorwiegend renalem Ausscheidungsmodus.</Pgraph><Pgraph>In unterschiedlichem Ausmaß werden die vorwiegend renal eliminierbaren Antibiotika neben der glomerulären Filtration auch tubulär sezerniert (z.B. Penicilline) oder reabsorbiert. Bei eingeschränkter Nierenfunktion soll die Dosierung dem Grad der Nierenfunktionseinschränkung entsprechend der Kreatinin-Clearance angepasst werden. Entscheidend für die Notwendigkeit einer Dosisanpassung ist</Pgraph><Pgraph><UnorderedList><ListItem level="1">der Anteil der renalen Elimination des Arzneimittels bei normaler Nierenfunktion,</ListItem><ListItem level="1">die Toxizität der Substanz, </ListItem><ListItem level="1">der Grad der Nierenfunktionseinschränkung und</ListItem><ListItem level="1">die Erhöhung der Kreatinin-Clearance über die Normwerte hinaus (z.B. bei verminderter Muskelmasse, Schwangerschaft oder im Frühstadium des Diabetes mellitus).</ListItem></UnorderedList></Pgraph><Pgraph>Grundsätzlich sind dabei vor allem die Dosierungsangaben der Hersteller zu beachten. Fehlen diese, soll die Anpassung des Dosierungsschemas bei Niereninsuffizienz durch die Berechnung der individuellen Eliminationsfraktion (Q) nach Dettli erfolgen <TextLink reference="11"></TextLink>, <TextLink reference="12"></TextLink>.</Pgraph><Pgraph>Hilfreiche Weblinks für die Dosisanpassung bei Nierenin<TextGroup><PlainText>s</PlainText></TextGroup>uffizienz: </Pgraph><Pgraph><UnorderedList><ListItem level="1"><Hyperlink href="http://www.infektio.de/antiinfektiva/dosierung-bei-niereninsuffizienz/">http://www.infektio.de/antiinfektiva/dosierung-bei-niereninsuffizienz/</Hyperlink></ListItem><ListItem level="1"><Hyperlink href="http://www.dosing.de/">http://www.dosing.de/</Hyperlink></ListItem></UnorderedList></Pgraph><Pgraph>Kritisch kranke Intensivpatienten nehmen in Bezug auf die substanzspezifische Pharmakokinetik eine Sonderstellung ein. Empfohlene Dosierungen und in Antibiogrammen ausgewiesene Sensibilitäten (sensibel, intermediär oder resistent getestet) beruhen auf der Annahme, dass die Pharmakokinetik des Arzneistoffs der eines „Normpatienten“ entspricht. Tatsächlich ist jedoch die Verteilung und Ausscheidungskapazität der Arzneistoffe beim kritisch Kranken sehr variabel und schwer vorhersehbar. Allein die Nierenfunktion von Patienten mit schweren Infektionen zeigt eine große inter- und intraindividuelle Variabilität, so dass die Arzneistoff-Clearance und damit die optimale Dosierung überwiegend renal ausgeschiedener Antiinfektiva um den Faktor 10 variieren kann <TextLink reference="13"></TextLink>. Dieses Problem ist nicht nur bei Beta-Lactam-Antibiotika <TextLink reference="13"></TextLink>, sondern auch bei Reservesubstanzen wie z.B. Linezolid <TextLink reference="14"></TextLink> klinisch apparent. In einem Übersichtsartikel werden hilfreiche Hinweise zur individualisierten Dosierung von Antiinfektiva (z.B. webbasierte Kalkulationsprogramme, z.B. CADDy [Calculator to Approximate Drug Dosing in Dialysis]) bei schwerkranken Intensivpatienten gegeben <TextLink reference="6"></TextLink>. Patienten mit Organersatzverfahren (z.B. Nierenersatzverfahren [Hämodialyse, Hämofiltration] <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="15"></TextLink>, ECMO <TextLink reference="16"></TextLink>, ECLS) stellen hier eine besondere Herausforderung dar.</Pgraph><Pgraph>Im Unterschied zur Kreatinin-Clearance bei Niereninsuffizienz sind klinische Scores bei Leberinsuffizienz (Child-Pugh-Score, MELD-Score) keine guten Prädiktoren für die Beurteilung der Arzneimittelmetabolisierung und -elimination.</Pgraph><Pgraph>Lebererkrankungen haben einen unterschiedlichen, schwer vorhersehbaren Einfluss auf die einzelnen Cytochrom-P450-Isoenzyme. Die existierenden Tests lassen lediglich die grobe Beurteilung der Funktion der einzelnen Isoenzyme zu. Die Reduktion der hepatischen Clearance und die damit verbundene Notwendigkeit der Dosisanpassung kann für Antibiotika relevant sein, die nahezu ausschließlich durch die Leberenzyme metabolisiert werden, vorwiegend solche mit hoher Lipophilie und geringer <TextGroup><PlainText>Polarität</PlainText></TextGroup>, die über die Niere schlecht eliminiert werden können (Antibiotika mit hoher extrarenaler Clearance: Clindamycin, Tedizolid, Chloramphenicol und Minocyclin). Eine höhergradige Leberinsuffizienz mit einer verminderten Metabolisierungsleistung muss auch bei der Dosierung von anderen Tetracyclinen, Clavulansäure, Flucloxacillin, Makroliden oder Streptograminen beachtet werden. Für Antibiotika mit hoher präsystemischer Eliminationsrate („First-Pass-Effekt“) kann bei eingeschränkter Leberfunktion die Bioverfügbarkeit nach oraler Gabe und damit die Plasmakonzentration signifikant ansteigen (z.B. Ciprofloxacin).</Pgraph><Pgraph>Für alle Stadien der Nieren- und Leberinsuffizienz gilt, dass die Loading-Dose (Initialdosis), die vom Verteilungsvolumen abhängig ist, identisch mit der von Nieren- oder Lebergesunden sein sollte. Bei initial reduzierter Dosis der Antibiotika kann es sonst unter Umständen mehrere Tage dauern, bis eine wirksame Konzentration erreicht wird. Da der Erfolg der Antibiotika-Therapie vor allem von der initialen Auswahl und einer adäquaten Dosierung abhängt, würde dies den Therapieerfolg gefährden.</Pgraph><Pgraph>Eine besondere pharmakotherapeutische Schwierigkeit stellt die Dosierung von Antibiotika bei Patienten mit Übergewicht dar. Die Kinetik zahlreicher Antibiotika ist aufgrund ungewöhnlicher Verteilungsprozesse bei diesen Patienten zum Teil unvorhersehbar. Dabei gibt es keine klare Beziehung zwischen der Lipophilie der Substanzen und ihrer Verteilung bei adipösen Patienten. Verändertes Verteilungsvolumen, Clearance, Probleme bei der Einschätzung der Nierenfunktion mithilfe von Kreatinin-Clearance sind nur einige Gründe, die dazu führen, dass übergewichtige Patienten mit Standarddosierungen von Antibiotika oft inadäquat versorgt werden. Subtherapeutische Konzentrationen können dann zum klinischen Therapieversagen und zur Resistenzentwicklung führen, während supratherapeutische/zu hohe Konzentrationen in der Regel zu unerwünschten Nebenwirkungen führen (eine Ausnahme stellen Aminoglykoside dar). Da grundsätzlich mit einem erhöhten Verteilungsvolumen und erhöhter Clearance bei diesen Patienten zu rechnen ist, ist eine gewichtsadaptierte Dosisanpassung notwendig. Welches Gewicht (TBW – total body weight, IBW – ideal body weight, LBW – lean body weight oder ABW – adju<TextGroup><PlainText>st</PlainText></TextGroup>ed body weight) als Grundlage für die Dosisberechnung herangezogen werden sollte, ist sowohl abhängig vom Antibiotikum selbst (z.B. bei Tigecyclin mit einem Verteilungsvolumen von 7 bis 10 l/kg <TextLink reference="17"></TextLink>) als auch von der Art und Dauer der Gabe <TextLink reference="18"></TextLink>, <TextLink reference="19"></TextLink>, <TextLink reference="20"></TextLink>, <TextLink reference="21"></TextLink>.</Pgraph><Pgraph>Hydrophile Antibiotika (Beta-Lactame, Aminoglykoside, Glykopeptide) <TextLink reference="22"></TextLink> verteilen sich weniger gut im Fettgewebe. Beim Dosieren dieser Antibiotika wird in der Regel das IBW oder ABW herangezogen <TextLink reference="23"></TextLink>. Die Verwendung des TBW kann hier zu Überdosierungen führen. Dagegen weisen lipophile Antibiotika (Fluorchinolone, Makrolide, Clindamycin, Tetracycline, Tigecyclin, Cotrimoxazol, Rifampicin, Chloramphenicol) <TextLink reference="22"></TextLink> ein höheres Verteilungsvo<TextGroup><PlainText>lu</PlainText></TextGroup>men auf. Folglich führt vermehrtes Fettgewebe bei adipösen Patienten auch zu einer Erhöhung des Verteilungsvolumens gegenüber normalgewichtigen Patienten. Tendenziell kann hier zum Dosieren das TBW verwendet werden <TextLink reference="23"></TextLink>. Zu beachten ist, dass sich der Grad der Hydrophilie bzw. Lipophilie innerhalb der beiden Gruppen (hydrophile und lipophile Antibiotika) von Antibiotikum zu Antibiotikum unterscheidet.</Pgraph><Pgraph>Bei besonderen Patientengruppen (solchen mit Mukoviszidose, Sepsis, Neutropenie, Verbrennungen oder hohem Körpergewicht) wird ein therapeutisches Drug-Monitoring (TDM) empfohlen <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>, <TextLink reference="10"></TextLink>, jedoch stehen nur für wenige Antibiotika schnelle Tests zur Verfügung (z.B. für Aminoglykoside, Glykopeptide). Besondere Dosierungsrichtlinien sind bei der vorgenannten Patientenklientel zu beachten. Die unterschiedlichen pharmakokinetischen Charakteristika der einzelnen Substanzen sind in <TextGroup><PlainText>Tabelle 1 </PlainText></TextGroup><ImgLink imgNo="1" imgType="table"/> zusammengefasst.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Interaction between pharmacokinetics and pharmacodynamics"> <MainHeadline>Interaction between pharmacokinetics and pharmacodynamics</MainHeadline><Pgraph>Since insufficient data is available on the concentration profiles at the site of infection, the pharmacokinetic evaluation of the various substances is usually carried out today using the different plasma concentrations; in severely ill intensive care patients, site concentrations may differ from the measurements in the primary compartment (serum, plasma) (especially in infections in deep compartments: lungs, bones, soft tissues) <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>. Depending on the mechanism of action, different indices are recommended for the different groups of active ingredients to manage treatment.</Pgraph><Pgraph>The differences in the pharmacodynamic profile of the antibiotic groups are also explained by their different modes of action – concentration-dependent effect of fluoroquinolones, aminoglycosides, tetracyclines and glycylcyclines (tigecycline) and the time-dependent (non concentration-dependent) effect of beta-lactam antibiotics, lincosamides and macrolides (Table 3 <ImgLink imgNo="3" imgType="table"/>). In the case of aminoglycosides, fluoroquinolones and cyclic lipopeptides (daptomycin), it has been shown that the ratio of peak concentration (C<Subscript>max</Subscript>) to the minimal inhibitory concentration (MIC) of the pathogen correlates with treatment success. For beta-lactam antibiotics, on the other hand, it is the percentage of the dosing interval in which the plasma concentration is above the pathogen MIC (t>MIC or %t>MIC). For fluoroquinolones and cyclic lipopeptides (daptomycin), the quotient of AUC (area under the curve) and MIC are considered predictive (the area under the 24-hour concentration time curve relative to the MIC: AUC<Subscript>24</Subscript>/MIC). This also applies to the group of glycopeptides. Previous findings on oxazolidinones (linezolid, tedizolid) indicate that both concentration and duration of exposure are relevant. The validation of these models for humans has been shown for some antibiotic groups.</Pgraph><Pgraph>In particular, in immunosuppressed patients and in infections in hard to reach compartments (abscesses, osteomyelitis, meningitis, necrotizing infections, see also <TextGroup><PlainText>Table 2 </PlainText></TextGroup><ImgLink imgNo="2" imgType="table"/>), the consideration of PK/PD indices in the choice of dosage regimen is of crucial importance. Also, the pharmacokinetic characteristics in the critically ill – which are affected by their hyperdynamic circulatory situation, endothelial damage, increased capillary permeability, hypoalbuminemia, extracorporeal circuits, intravenous administration of large amounts of fluid or administration of vasopressors – can contribute to an increased volume of distribution and by increasing renal perfusion in the absence of relevant organ dysfunction to an increased clearance of hydrophilic antibiotics and reduction of their plasma concentration <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>. For such seriously ill patients, other PD indices may be important besides MIC. For treatment success in certain groups of pathogens (non-fermenters, e.g. <Mark2>Pseudomonas aeruginosa</Mark2>) including the avoidance of resistance development, concentration profiles may be more favorable in which the site concentrations remain well above the MIC (corresponds to MPC, mutant prevention concentration) <TextLink reference="4"></TextLink>, <TextLink reference="7"></TextLink>. </Pgraph><Pgraph>The data on PK/PD correlations offer the possibility of adjusting the dosage individually using therapeutic drug monitoring (TDM), especially in high-risk populations (such as critically ill patients, geriatric patients, patients with organ failure, infections with multidrug-resistant pathogens [e.g. extended-spectrum beta-lactamase (ESBL) producers]) <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>, <TextLink reference="10"></TextLink>.</Pgraph><Pgraph>Clearance and volume of distribution determine the half-life of a substance. These parameters also co-determine the time the plasma concentration is above the MIC and for the total exposure (AUC) and play an important role in the calculation of the dosing interval.</Pgraph><Pgraph>Decreased function of the drug-eliminating organs (especially the kidneys and the liver) results in reduced clearance of antibiotics and prolongs the half-life, which may be one reason for the increased rate of adverse effects. The relevance of impaired renal and hepatic function plays a lesser role for antibiotics with a wide therapeutic range (broad concentration range between the effective and the toxic levels, for instance for penicillins, cephalosporins, carbapenems, macrolides, lincosamides, fluoroquinolones, linezolid) than for antibiotics with a narrow therapeutic range (such as aminoglycosides or vancomycin). Nevertheless, in intensive care patients it has been shown that increased plasma levels of beta-lactam antibiotics are associated with a poorer neurological outcome <TextLink reference="5"></TextLink>. In addition to the microbiological efficacy, the extent of renal and extrarenal elimination as well as any potential nephro- and/or hepatotoxic potential of the antibiotics themselves or their metabolites play an important role in the selection of suitable antibiotics. These antibiotics (potentially nephrotoxic: aminoglycosides, vancomycin, teicoplanin, telavancin; potentially hepatotoxic: amoxicillin/clavulanic acid, flucloxacillin, fluoroquinolones, tetracyclines, rifampicin) should only be administered in life-threatening situations if the corresponding organ has impaired function. Possible risks due to the accumulation of potential toxic metabolites in patients with pronounced renal and hepatic insufficiency should also be considered. In principle, antibiotics with high extrarenal elimination should be selected in cases of impaired renal function and, in hepatic insufficiency, antibiotics with a predominantly renal excretion mode.</Pgraph><Pgraph>Antibiotics which are predominantly eliminated via the kidneys to varying degrees are also secreted by glomerular or tubular filtration (e.g. penicillins) or reabsorbed. If renal function is impaired, the dosage should be adjusted to the degree of renal impairment according to creatinine clearance. The following are crucial in determining the need for dose adjustment:</Pgraph><Pgraph><UnorderedList><ListItem level="1">the proportion of renal elimination of the drug in normal renal function,</ListItem><ListItem level="1">the toxicity of the substance, </ListItem><ListItem level="1">the degree of renal impairment; and</ListItem><ListItem level="1">the increase of creatinine clearance beyond normal levels (for example with reduced muscle mass, pregnancy or early stage diabetes mellitus).</ListItem></UnorderedList></Pgraph><Pgraph>In general the dosage specifications of the manufacturers should be followed. If these are not available, the dosing regimen for renal insufficiency should be adjusted by calculating the individual elimination fraction (Q) according to Dettli <TextLink reference="11"></TextLink>, <TextLink reference="12"></TextLink>.</Pgraph><Pgraph>Helpful links for dose adjustment in renal insufficiency: </Pgraph><Pgraph><UnorderedList><ListItem level="1"><Hyperlink href="http://www.infektio.de/antiinfektiva/dosierung-bei-niereninsuffizienz/">http://www.infektio.de/antiinfektiva/dosierung-bei-niereninsuffizienz/</Hyperlink></ListItem><ListItem level="1"><Hyperlink href="http://www.dosing.de/">http://www.dosing.de/</Hyperlink></ListItem></UnorderedList></Pgraph><Pgraph>Critically ill intensive care patients have a special status in terms of substance-specific pharmacokinetics. Recommended dosages and sensitivities (tested as sensitive, intermediate or resistant) are based on the assumption that the pharmacokinetics of the drug are equivalent to those of a “standard patient”. In fact, however, the distribution and elimination capacity of drugs in the critically ill is very variable and difficult to predict. The renal function of patients with severe infections alone shows great inter- and intra-individual variability, so that the drug clearance and thus the optimal dosage of predominantly renally excreted anti-infective drugs can vary by a factor of 10 <TextLink reference="13"></TextLink>. This problem is not only clinically apparent with beta-lactam antibiotics <TextLink reference="13"></TextLink> but also with reserve substances such as linezolid <TextLink reference="14"></TextLink>. A review article provides helpful guidance on individualized dosing of anti-infective agents (e.g. web-based calculation programs such as CADDy [Calculator to Approximate Drug Dosing in Dialysis] in seriously ill intensive care patients <TextLink reference="6"></TextLink>. Patients with organ replacement procedures (such as renal replacement procedures [hemodialysis, hemofiltration] <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="15"></TextLink>, ECMO <TextLink reference="16"></TextLink>, ECLS) present a particular challenge here.</Pgraph><Pgraph>Unlike creatinine clearance in renal insufficiency, clinical scores in hepatic insufficiency (Child-Pugh score, MELD score) are not good predictors of drug metabolization and elimination.</Pgraph><Pgraph>Liver diseases have a different, unpredictable influence on the individual cytochrome P450 isoenzymes. Existing tests allow only a rough assessment of the function of the individual isoenzymes. The reduction in hepatic clearance and the associated need for dose adjustment may be relevant to antibiotics that are almost exclusively metabolized by liver enzymes, predominantly those with high lipophilicity and low polarity that can be poorly eliminated via the kidney (antibiotics with high extrarenal clearance: clindamycin, tedizolid, chloramphenicol and minocycline). When dosing with other tetracyclines, clavulanic acid, flucloxacillin, macrolides or streptogramins, higher grade hepatic insufficiency with reduced metabolization performance must also be considered. For antibiotics with a high presystemic elimination rate (e.g. ciprofloxacin), hepatic impairment may significantly increase the bioavailability after oral administration and thus the plasma concentration.</Pgraph><Pgraph>For all stages of renal and hepatic insufficiency, the loading dose (initial dose), which depends on the volume of distribution, should be identical to that for a healthy kidney or liver. Otherwise, initially reduced doses of antibiotics may take several days to reach an effective level. Since the success of antibiotic treatment mainly depends on the initial selection and an adequate dosage, this would jeopardize treatment success.</Pgraph><Pgraph>The dosage of antibiotics in overweight patients is a particular pharmacotherapeutic problem. The kinetics of many antibiotics are sometimes unpredictable due to unusual distributional processes in these patients. There is no clear relationship between the lipophilicity of the substances and their distribution in obese patients. Altered volume of distribution, clearance and problems in assessing kidney function using creatinine clearance are just some of the reasons that often cause overweight patients to be inadequately treated with standard doses of antibiotics. Subtherapeutic concentrations may then lead to clinical treatment failure and development of resistance, while supratherapeutic/excessively high concentrations usually lead to undesirable side effects (with the exception of aminoglycosides). Since an increased volume of distribution and increased clearance is generally to be expected in these patients, a weight-adapted dose adjustment is necessary. Which weight (TBW – total body weight, IBW – ideal body weight, LBW – lean body weight or ABW – adjusted body weight) should be used as the basis for the dose calculation is dependent both on the antibiotic itself (e.g. in tigecycline with a distribution volume of 7 to 10 l/kg <TextLink reference="17"></TextLink>) as well as the type and duration of administration <TextLink reference="18"></TextLink>, <TextLink reference="19"></TextLink>, <TextLink reference="20"></TextLink>, <TextLink reference="21"></TextLink>.</Pgraph><Pgraph>Hydrophilic antibiotics (beta-lactams, aminoglycosides, glycopeptides) <TextLink reference="22"></TextLink> are less well distributed in adipose tissue. When dosing these antibiotics IBW or ABW are usually used <TextLink reference="23"></TextLink>. Using TBW can lead to overdoses. In contrast, lipophilic antibiotics (fluoroquinolones, macrolides, clindamycin, tetracyclines, tigecycline, cotrimoxazole, rifampicin, chloramphenicol) <TextLink reference="22"></TextLink> have a higher volume of distribution. Consequently, increased adipose tissue in obese patients also leads to an increase in the volume of distribution compared to patients with normal weight. TBW tends to be used for dosing in this case <TextLink reference="23"></TextLink>. It should be noted that the degree of hydrophilicity or lipophilicity within the two groups (hydrophilic and lipophilic antibiotics) differs from antibiotic to antibiotic.</Pgraph><Pgraph>For special patient populations (those with CF, sepsis, neutropenia, burns, or high body weight) Therapeutic Drug Monitoring (TDM) is recommended <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="9"></TextLink>, <TextLink reference="10"></TextLink> but only a few antibiotics have rapid tests available (for example, aminoglycosides, glycopeptides). Special dosage guidelines must be observed in the aforementioned patient groups. The different pharmacokinetic characteristics of the individual substances are summarized in <TextGroup><PlainText>Table 1 </PlainText></TextGroup><ImgLink imgNo="1" imgType="table"/>.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Therapeutisches Drug-Monitoring"> <MainHeadline>Therapeutisches Drug-Monitoring</MainHeadline><Pgraph>Viele Antibiotika sind durch erhebliche inter- und intraindividuelle Unterschiede der pharmakokinetischen Eigenschaften, vor allem im Eliminationsverhalten und Verteilungsvolumen, gekennzeichnet. Dies trifft im besonderen Maße auf Intensivpatienten mit schwerer Sepsis, septischem Schock und konsekutivem Multiorganversagen und starken Veränderungen in den Verteilungsräumen (z.B. kapilläres Leck und durch Infusionsbehandlungen) zu <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>. Dadurch können die resultierenden Plasmakonzentrationen nach Standarddosen in weiten Bereichen streuen <TextLink reference="13"></TextLink>, wodurch einerseits die Gefahr der Unterdo<TextGroup><PlainText>s</PlainText></TextGroup>ierung mit unzureichender therapeutischer Wirkung, andererseits überhöhte Plasmaspiegel mit dem Risiko unerwünschter toxischer Wirkungen drohen. Ziel des therapeutischen Drug-Monitorings (TDM) ist es, unter Berücksichtigung pharmakokinetischer Prinzipien und Messungen der Arzneimittelkonzentration im Patientenblut die individuell optimale Dosierung für den Patienten zu finden <TextLink reference="6"></TextLink>, <TextLink reference="7"></TextLink>, <TextLink reference="8"></TextLink>.</Pgraph><Pgraph>Voraussetzung bzw. Indikation für die Durchführung eines TDM sind vor allem:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Für therapeutische und toxische Wirkungen existieren Konzentrations-Wirkungs-Beziehungen.</ListItem><ListItem level="1">Die Substanz hat einen engen therapeutischen Bereich und schon relativ geringfügige Überschreitungen dieses Konzentrationsbereichs können zu toxischen Wirkungen führen.</ListItem><ListItem level="1">Die Pharmakokinetik des Wirkstoffs unterliegt erheblichen intra- und interindividuellen Schwankungen, vor allem bei Intensivpatienten mit schwerer Sepsis und septischem Schock.</ListItem><ListItem level="1">Pharmakokinetische Zielgrößen (C<Subscript>max</Subscript>, C<Subscript>min</Subscript>, AUC) sind bekannt.</ListItem><ListItem level="1">Ausreichend sensitive und mit vertretbarem Aufwand realisierbare analytische Methoden zur Konzentrationsbestimmung sind verfügbar.</ListItem></UnorderedList></Pgraph><Pgraph>Für viele Antibiotika, z.B. Penicilline und Cephalosporine, ist die Gefahr unerwünschter toxischer Wirkungen eher gering, da sie eine relativ große therapeutische Breite besitzen. Für diese Antibiotika ist eine blutspiegelorientierte Therapie nur bei bestimmten Patientengruppen (z.B. Intensivpatienten) empfehlenswert <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>, <TextLink reference="13"></TextLink>. In einer gemischten Intensivpatientenklientel ist in 20–30% der Fälle eine Dosisanpassung notwendig <TextLink reference="4"></TextLink>, <TextLink reference="8"></TextLink>. Intensivpatienten mit einer erhöhten Kreatinin-Clea<TextGroup><PlainText>r</PlainText></TextGroup>ance sind für eine relevante Unterdosierung besonders gefährdet <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="24"></TextLink>, <TextLink reference="25"></TextLink>. Die Messung von Beta-Lactam-Konzentrationen ist bisher nicht weit verbreitet, da sich dezidierte PK/PD-Ziele sowie Strategien zur Dosisanpassung aktuell im wissenschaftlichen Diskurs befinden <TextLink reference="6"></TextLink>, <TextLink reference="10"></TextLink>. Die Messung erfolgt überwiegend mit chromatographischen Verfahren. Kommerzielle Messverfahren sind in Deutschland nicht verfügbar <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>. Zu den Arzneimitteln, für deren sicheren Einsatz ein TDM dringend empfohlen wird, gehören die Aminoglykoside und Glykopeptide. Unter Berücksichtigung verschiedener Patientenkollektive sind in Tabelle 4 <ImgLink imgNo="4" imgType="table"/> Empfehlungen zu den Zielbereichen für den Tal- und Spitzenspiegel der am häufigsten eingesetzten Aminoglykoside und Glykopeptide aufgeführt.</Pgraph><Pgraph>Bei der Therapie mit Aminoglykosiden hat sich die Einmalgabe der gesamten Tagesdosis durchgesetzt, verbunden mit Erhöhung der klinischen Effektivität, geringerer Toxizität und ökonomischen Vorteilen <TextLink reference="26"></TextLink>, <TextLink reference="27"></TextLink>, <TextLink reference="28"></TextLink>, <TextLink reference="29"></TextLink>, <TextLink reference="30"></TextLink>, <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>, <TextLink reference="34"></TextLink>, <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>. Unter Beachtung anerkannter PK/PD-Parameter werden für Aminoglykoside Spitzenspiegel deutlich oberhalb der MHK des Erregers (C<Subscript>max</Subscript>/MHK>10) angestrebt <TextLink reference="37"></TextLink>, <TextLink reference="38"></TextLink>. Die mittlere MHK von Gentamicin liegt für Erreger mit reduzierter Empfindlichkeit (z.B. für <Mark2>Pseudomonas aeruginosa</Mark2>) bei 2 mg/l; somit ergeben sich anzustrebende Spitzenspiegel von mindestens 20 mg/l <TextLink reference="39"></TextLink>. </Pgraph><Pgraph>Bei der Behandlung von Endokarditiden und neutropenischen Patienten ist die Einmalgabe in den meisten Fällen ausreichend. Bei schwerwiegenden Endokarditiden (Enterokokken, Herzklappenprothesen) wird von der Einmalgabe abgeraten und eine Mehrfachgabe empfohlen, z.B. in Kombination mit einem synergistisch wirkenden, an der Zellwand angreifenden Antibiotikum <TextLink reference="40"></TextLink>.</Pgraph><Pgraph>Bei der Therapie mit den Glykopeptid-Antibiotika Vancomycin und Teicoplanin werden entsprechend ihrer pharmakodynamischen Parameter dauerhafte Konzentrationen oberhalb der MHK der betreffenden Erreger angestrebt. Im Rahmen des TDM werden in der Regel die Talspiegel kontrolliert <TextLink reference="41"></TextLink>. Bei Behandlung von lebensbedrohlichen Infektionen (bei Meningitis und Pneumonie) und bei Erregern mit reduzierter Empfindlichkeit sollen Vancomycin-Talspiegel von 15–20 mg/l angestrebt werden <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>, <TextLink reference="44"></TextLink>. Dabei ist jedoch die erhöhte Gefahr von Nephrotoxizität ab einem Vancomycin-Talspiegel von >15 mg/l zu beachten <TextLink reference="45"></TextLink>. Hinweise aus der aktuellen Literatur sprechen dafür, dass die kontinuierliche Applikation von Vancomycin die Wahrscheinlichkeit nephrotoxischer Nebenwirkungen senkt <TextLink reference="46"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="48"></TextLink>, <TextLink reference="49"></TextLink>. </Pgraph><Pgraph>Bei der Behandlung von Knochen- oder Protheseninfektionen werden für Teicoplanin-Talspiegel von 20–25 mg/l empfohlen <TextLink reference="50"></TextLink>. Wird Teicoplanin zur Behandlung von bakterieller Endokarditis verwendet, sollten die Talspiegel bei mindestens 30–40 mg/l liegen <TextLink reference="51"></TextLink>. Talspiegel oberhalb 60 mg/l werden als toxisch angesehen <TextLink reference="52"></TextLink>.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Therapeutic drug monitoring"> <MainHeadline>Therapeutic drug monitoring</MainHeadline><Pgraph>Many antibiotics are characterized by significant inter- and intra-individual differences in pharmacokinetic properties, especially in elimination behavior and volume of distribution. This is especially true in intensive care patients with severe sepsis, septic shock and consecutive multiple organ failure and profound changes in distribution spaces (e.g. capillary leak and infusion treatments) <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>. As a result, even standard doses can result in a wide range of plasma concentrations <TextLink reference="13"></TextLink>, which, on the one hand, threatens the risk of under-dosing with insufficient therapeutic effect, on the other hand excessive plasma levels with the risk of undesirable toxic effects. The aim of therapeutic drug monitoring (TDM) is to find the optimal individual dosage for the patient taking into account pharmacokinetic principles and measurements of the drug concentration in the patient’s blood <TextLink reference="6"></TextLink>, <TextLink reference="7"></TextLink>, <TextLink reference="8"></TextLink>.</Pgraph><Pgraph>Prerequisites or indications for conducting TDM above all are:</Pgraph><Pgraph><UnorderedList><ListItem level="1">Therapeutic and toxic effects are in a concentration related cause and effect relationship.</ListItem><ListItem level="1">The substance has a narrow therapeutic range and exceeding the concentration range by even relatively degree can lead to toxic effects.</ListItem><ListItem level="1">The pharmacokinetics of the drug are subject to significant intra- and inter-individual variability, especially in intensive care patients with severe sepsis and septic shock.</ListItem><ListItem level="1">Pharmacokinetic target parameters (C<Subscript>max</Subscript>, C<Subscript>min</Subscript>, AUC) are known.</ListItem><ListItem level="1">Sufficiently sensitive methods for determining concentration are available involving a reasonable amount of effort.</ListItem></UnorderedList></Pgraph><Pgraph>For many antibiotics, e.g. penicillins and cephalosporins, the risk of unwanted toxic effects is rather low, since they have a relatively large therapeutic range. For these antibiotics, treatment based on blood level is only recommended for certain patient groups (e.g. intensive care patients) <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>, <TextLink reference="13"></TextLink>. In a mixed intensive care group, dosage adjustment is necessary in 20–30% of cases <TextLink reference="4"></TextLink>, <TextLink reference="8"></TextLink>. Intensive care patients with elevated creatinine clearance are at particular risk of the associated under-dosing <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="24"></TextLink>, <TextLink reference="25"></TextLink>. The measurement of beta-lactam concentrations is currently not widespread, as dedicated PK/PD targets and dose-adjustment strategies are currently being debated in scientific circles <TextLink reference="6"></TextLink>, <TextLink reference="10"></TextLink>. The measurement is predominantly done by chromatography. Commercial measuring methods are not available in Germany <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>. Drugs where TDM is strongly recommended for their safe use include aminoglycosides and glycopeptides. Table 4 <ImgLink imgNo="4" imgType="table"/> gives recommendations on the target ranges for the peak and trough levels of the most commonly used aminoglycosides and glycopeptides taking into account different patient populations.</Pgraph><Pgraph>In treatment with aminoglycosides, single administration of the total daily dose has become more widespread, with increased clinical effectiveness, lower toxicity and economic advantages <TextLink reference="26"></TextLink>, <TextLink reference="27"></TextLink>, <TextLink reference="28"></TextLink>, <TextLink reference="29"></TextLink>, <TextLink reference="30"></TextLink>, <TextLink reference="31"></TextLink>, <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>, <TextLink reference="34"></TextLink>, <TextLink reference="35"></TextLink>, <TextLink reference="36"></TextLink>. Taking into account accepted PK/PD parameters, aminoglycoside peak levels well above the MIC of the pathogen (C<Subscript>max</Subscript>/MIC>10) are aimed for <TextLink reference="37"></TextLink>, <TextLink reference="38"></TextLink>. The mean MIC of gentamicin is 2 mg/l for pathogens with reduced sensitivity (e.g. for <Mark2>Pseudomonas aeruginosa</Mark2>); thus, peak levels of at least 20 mg/l should be aimed for <TextLink reference="39"></TextLink>. </Pgraph><Pgraph>In the treatment of endocarditis and neutropenic patients, single dose administration is sufficient in most cases. For severe endocarditis (enterococci, heart valve prostheses), single dose administration is not recommended and multiple administration recommended, for example in combination with a synergistic antibiotic attacking the cell wall <TextLink reference="40"></TextLink>.</Pgraph><Pgraph>In treatment with the glycopeptide antibiotics vancomycin and teicoplanin the aims are permanent concentrations above the MIC of the relevant pathogens in accordance with their pharmacodynamic parameters. As mandated by TDM, trough levels are monitored <TextLink reference="41"></TextLink>. For the treatment of life-threatening infections (meningitis and pneumonia) and reduced sensitivity agents, vancomycin trough levels of 15–20 mg/l should be the target <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink>, <TextLink reference="44"></TextLink>. However, the increased risk of nephrotoxicity above a vancomycin trough level >15 mg/l should be taken into account <TextLink reference="45"></TextLink>. Evidence from recent literature suggests that continuous administration of vancomycin reduces the likelihood of nephrotoxic side effects <TextLink reference="46"></TextLink>, <TextLink reference="47"></TextLink>, <TextLink reference="48"></TextLink>, <TextLink reference="49"></TextLink>. </Pgraph><Pgraph>For the treatment of bone or prosthetic infections, teicoplanin trough levels of 20–25 mg/l are recommended <TextLink reference="50"></TextLink>. When teicoplanin is used to treat bacterial endocarditis, trough levels should be at least 30–40 mg/l <TextLink reference="51"></TextLink>. Trough levels above 60 mg/l are considered toxic <TextLink reference="52"></TextLink>.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Kontinuierliche oder prolongierte Infusionen von Beta-Lactam-Antibiotika"> <MainHeadline>Kontinuierliche oder prolongierte Infusionen von Beta-Lactam-Antibiotika</MainHeadline><Pgraph>Beta-Lactam-Antibiotika entfalten eine effektive Wirkung, wenn möglichst dauerhaft während der Wachstumsphase der Zellwand die MHK der Erreger überschritten wird. Initial nimmt die Bakterizidie mit steigenden Konzentrationen des Antibiotikums bis zum 4- bis 5-fachen der MHK zu, höhere Wirkspiegel können jedoch das Therapieer<TextGroup><PlainText>geb</PlainText></TextGroup>nis nicht verbessern. Dieser pharmakokinetisch-pharmakodynamische Zusammenhang wird als zeitab<TextGroup><PlainText>h</PlainText></TextGroup>ängige (nicht-konzentrationsabhängige) Bakterizidie beschrieben. Bei Beta-Lactam-Antibiotika sollte die Konzentration des ungebundenen Antibiotikums innerhalb eines Dosierungsintervalls für mindestens 40–60% dieser Zeit die MHK der Erreger am Infektionsort überschreiten <TextLink reference="53"></TextLink>, wobei etwa 40% für Carbapeneme gelten und die höheren Werte für Cephalosporine; Penicilline liegen dazwischen. Diese Daten leiten sich aus tierexperimentellen Untersuchungen ab. Ergebnisse klinischer Studien bei Intensivpatienten sprechen dafür, dass 100% der Zeit oberhalb der MHK das Outcome verbessern können <TextLink reference="54"></TextLink>, <TextLink reference="55"></TextLink>, <TextLink reference="56"></TextLink>, <TextLink reference="57"></TextLink>, <TextLink reference="58"></TextLink>. Da gerade bei Intensivpatienten mit schweren Infektionen in tiefen Kompartimenten die im Rahmen des TDM gemessenen Plasmakonzentrationen nicht den Wirkortkonzentrationen entsprechen, empfehlen einige Experten als PK/PD-Ziel den Plasmaspiegel 100% des Dosierungsintervalls oberhalb des 4- bis <TextGroup><PlainText>5-f</PlainText></TextGroup>achen der MHK zu halten <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>. </Pgraph><Pgraph>Die pharmakokinetischen Daten der Beta-Lactam-Antibiotika zeigen untereinander keine große Variabilität. Beta-Lactam-Antibiotika verteilen sich nach parenteraler Gabe rasch im Extrazellularraum. Im Fließgleichgewicht werden ähnliche Konzentrationen nach einer intermittierenden Gabe und nach einer Bolusgabe mit anschließender kontinuierlicher Infusion erreicht <TextLink reference="59"></TextLink>, <TextLink reference="60"></TextLink>, <TextLink reference="61"></TextLink>, <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink>, <TextLink reference="64"></TextLink>.</Pgraph><Pgraph>Die Dosierungsempfehlungen der Hersteller sehen in der Regel eine 2- bis 4-malige (1- bis 6-malige) Gabe des Beta-Lactam-Antibiotikums in Abhängigkeit von pharmakokinetischen Parametern vor. Dadurch werden im Rahmen zugelassener und durch klinische Studien gesicherter Indikationen meist ausreichende freie Wirkspiegel erreicht, die die MHK sensibler Erreger überschreiten. Allerdings kann durch die intermittierende Applikation das Ziel einer möglichst dauerhaften Überschreitung der MHK des Erregers am Ort der Infektion oft nicht erreicht werden, wie PK/PD-Simulationen, experimentelle und auch klinische Untersuchungen zeigen <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>. Dies gilt insbesondere bei Patienten mit hohen extrazellulären Verteilungsräumen und einer gesteigerten Clearance-Rate. Hierzu zählen vor allem Patienten mit einer hyperdynamen Kreislaufsituation und einem kapillären Leck, z.B. im Rahmen einer Sepsis, Patienten mit zystischer Fibrose, Drainagen, Blutungen, großflächigen Verbrennungen, Aszites, schwerer Pankreatitis, Patienten mit einem BMI>30 kg/m<Superscript>2</Superscript>, Herzinsuffizienz, Ödemen, Hämofiltration (in Abhängigkeit von der Bilanz), Dialyse-Patienten (vor Dialyse) und Schwangere <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>. Dagegen haben exsikkierte Patienten, Dialyse-Patienten nach der Dialyse und Patienten mit Volumenrestriktionen ein niedrigeres Verteilungsvolumen als Normalpatienten. Für Risikopatienten und in der Geriatrie wird daher eine Individualisierung der Antibiotika-Therapie gefordert <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="65"></TextLink>, <TextLink reference="66"></TextLink>, <TextLink reference="67"></TextLink>, <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink>, <TextLink reference="70"></TextLink>, <TextLink reference="71"></TextLink>, <TextLink reference="72"></TextLink>, <TextLink reference="73"></TextLink>, <TextLink reference="74"></TextLink>, <TextLink reference="75"></TextLink>, <TextLink reference="76"></TextLink>, <TextLink reference="77"></TextLink>.</Pgraph><Pgraph>Empfehlungen zur prolongierten (Applikation über <TextGroup><PlainText>3–4 S</PlainText></TextGroup>tunden) oder kontinuierlichen Gabe der Beta-Lac<TextGroup><PlainText>t</PlainText></TextGroup>am-Antibiotika basieren auf theoretischen Überlegungen, die von experimentellen Untersuchungen oder Simulationen unterstützt werden. Klinische Untersuchungen konnten einen Vorteil der prolongierten bzw. kontinuierlichen Gabe mit länger andauernden Serumspiegeln oberhalb der MHK auch bei niedrigeren Tagesdosierungen <TextLink reference="78"></TextLink>, <TextLink reference="79"></TextLink>, <TextLink reference="80"></TextLink>, <TextLink reference="81"></TextLink>, <TextLink reference="82"></TextLink>, <TextLink reference="83"></TextLink>, <TextLink reference="84"></TextLink>, <TextLink reference="85"></TextLink>, <TextLink reference="86"></TextLink>, <TextLink reference="87"></TextLink>, <TextLink reference="88"></TextLink>, <TextLink reference="89"></TextLink>, <TextLink reference="90"></TextLink>, <TextLink reference="91"></TextLink>, <TextLink reference="92"></TextLink>, <TextLink reference="93"></TextLink>, <TextLink reference="94"></TextLink>, <TextLink reference="95"></TextLink>, <TextLink reference="96"></TextLink> und eine vergleichbare Effektivität und Sicherheit <TextLink reference="71"></TextLink>, <TextLink reference="97"></TextLink>, <TextLink reference="98"></TextLink> hinsichtlich der klinischen und mikrobiologischen Wirksamkeit belegen. Vorteile der prolongierten Antibiotika-Applikation wurden vor allem bei schwerkranken Intensivpatienten (APACHE II Score >17) gezeigt <TextLink reference="99"></TextLink>. Über eine Überlegenheit der kontinuierlichen beziehungsweise intermittierenden Gabe gehen derzeit die Meinungen noch auseinander <TextLink reference="100"></TextLink>, <TextLink reference="101"></TextLink>, <TextLink reference="102"></TextLink>, <TextLink reference="103"></TextLink>, <TextLink reference="104"></TextLink>. In einer aktuellen klinischen Untersuchung konnte kein Unterschied bezüglich der Letalität objektiviert werden <TextLink reference="105"></TextLink>. Eine weitere aktuelle Studie unterstrich jedoch eine verbesserte Heilungsrate unter kontinuierlicher Applikation <TextLink reference="106"></TextLink>. Dieses Ergebnis wird von einer aktuellen Metaanalyse noch einmal bestätigt <TextLink reference="107"></TextLink>. Die kontinuierliche Applikation von Beta-Lactam-Antibiotika ohne TDM ist nicht ohne Einschränkung zu empfehlen, da die Gefahr besteht, dauerhaft die MHK des Erregers zu unterschreiten. Ein Unterschreiten der MHK hat nicht nur eine mangelnde Wirksamkeit des Antibiotikums zur Folge, sondern kann auch die Selektion resistenter Mutanten begünstigen. Ein sicheres Erreichen von rationalen PK/PD-Zielen ist nur mit einem TDM sicherzustellen und somit bei der kontinuierlichen Applikation von essentieller Bedeutung. Die prolongierte Applikation ist vor diesem Hintergrund deutlich sicherer.</Pgraph><Pgraph>Beta-Lactam-Antibiotika sind nach der Zubereitung nur begrenzt stabil. Hierbei ist nicht nur der Grad der Degradation entscheidend, sondern vor allem die Art der Zersetzungsprodukte, die ein allergenes Potenzial besitzen. In zahlreichen Untersuchungen zur Stabilität der Substanzen wird diese Tatsache nur unzureichend beachtet. Danach gelten Lösungen von Beta-Lactam-Antibiotika innerhalb eines untersuchten Zeitraums als stabil, wenn deren Degradation den Wert von 10% unterschreitet. Das Ausmaß der Degradation ist abhängig von dem Lösungsmittel, dem Lichteinfluss, der Konzentration des Antibiotikums, der Art der Applikationshilfen sowie der Herstellung und Temperatur. Bei körpernaher Pumpenapplikation im Rahmen einer ambulanten parenteralen Antibiotika-Therapie (APAT) müssen wegen der erhöhten Umgebungswärme deutliche Stabilitätseinbußen berücksichtigt werden.</Pgraph><Pgraph>Von hoher praktischer Bedeutung ist die Verwendung des empfohlenen Lösungsmittels, um eine optimale Löslichkeit und Stabilität zu gewährleisten. So müssen fast ausnahmslos alle Penicilline (Trockensubstanzen) in Aqua ad injectabilia gelöst werden, um das Lösungsverhalten zu beschleunigen und eine Partikelfreiheit zu gewährleisten. Eine weitere Verdünnung ist danach in üblichen Infusionslösungen meist möglich. Bei vielen Beta-Lactam-Antibiotika ist eine Reihe von Inkompatibilitätsreaktionen mit anderen Arzneimitteln beschrieben, wenn sie im gleichen Infusionssystem verabreicht werden sollen. Die Angaben des Herstellers zur Kompatibilität müssen unbedingt beachtet werden.</Pgraph><Pgraph>Häufigste unerwünschte Arzneimittelwirkung der Penicilline sind Allergien und pseudoallergische Reaktionen. Ursache dieser Reaktionen ist das Vorliegen einer instabilen Beta-Lactam-Struktur oder spezifischer Seitenketten. Penicilline in Lösung sind in Abhängigkeit von ihren Seitenketten und dem pH-Wert unterschiedlich stabil. Die Abbauprodukte der Penicilline wirken als Haptene und können kovalente Bindungen mit körpereigenen Proteinen eingehen. Sie bilden einen Hapten-Protein-Komplex, der eine allergieerzeugende Immunantwort induzieren kann. Die Abbauprodukte der Penicilline haben ein erhebliches Allergisierungspotenzial. Weitere Informationen zum Thema Sicherheit können Kapitel 4 <TextLink reference="108"></TextLink> entnommen werden.</Pgraph><Pgraph>Art und Ausmaß der Degradation der Beta-Lactam-Antibiotika sind substanzabhängig. Acylaminopenicilline, <TextGroup><PlainText>Isoxazolyl</PlainText></TextGroup>penicilline, Cephalosporine und Aztreonam sind aufgrund ihrer Struktur in der Regel stabiler als Benzylpenicillin. Eine Ringöffnung ist jedoch auch bei Cephalosporinen durch nukleophilen oder (seltener) elektrophilen Angriff möglich, wie das Beispiel des Ceftazidims und anderer Cephalosporine zeigt <TextLink reference="109"></TextLink>. Die chemische Stabilität der Carbapeneme ist sehr unterschiedlich und hängt vor allem von der Konzentration der Lösung und von der Temperatur ab <TextLink reference="110"></TextLink>, <TextLink reference="111"></TextLink>. Zu den Stabilitätsdaten verschiedener Beta-Lactam-Antibiotika in Infusionslösungen gibt es sehr widersprüchliche Angaben. Hier sollte die Empfehlung des Herstellers des Produktes beachtet werden.</Pgraph><Pgraph>Linezolid weist wie die Beta-Lactam-Antibiotika bei Patienten mit schweren Infektionen eine hohe Variabilität der Serumkonzentrationen mit unzureichenden Blutspiegeln unter Standarddosierungskonzepten auf. Aktuelle Daten weisen darauf hin, dass auch hier eine kontinuierliche Applikation einen sinnvollen Beitrag leisten kann, um PK/PD-Ziele besser zu erreichen <TextLink reference="112"></TextLink>, <TextLink reference="113"></TextLink>.</Pgraph><SubHeadline>Fazit</SubHeadline><Pgraph><UnorderedList><ListItem level="1">Aufgrund pharmakokinetischer/pharmakodynamischer Überlegungen ist eine prolongierte oder kontinuierliche Infusion von Beta-Lactam-Antibiotika der intermittierenden Gabe hinsichtlich des Therapieziels, möglichst dauerhaft die MHK der Erreger zu überschreiten, überlegen. </ListItem><ListItem level="1">Klinische Daten zur signifikanten Überlegenheit dieses Therapieregimes liegen in geringer Zahl vor.</ListItem><ListItem level="1">Kontinuierliche und intermittierende Infusionen eines Beta-Lactam-Antibiotikums zeigen ein vergleichbares Nebenwirkungsprofil.</ListItem><ListItem level="1">Empfohlen wird die prolongierte/kontinuierliche Gabe bei Patienten, deren pharmakokinetische Parameter (Verteilungsvolumen, Clearance) von Normalpopulationsdaten deutlich abweichen (z.B. Patienten mit Sepsis und septischem Schock, zystischer Fibrose oder Patienten mit schweren Infektionen durch Erreger mit verminderter Empfindlichkeit). Die kontinuierliche Applikation ist nur unter TDM zu empfehlen. Die prolongierte Gabe eines Beta-Lactam-Antibiotikums ist auch ohne TDM sicher durchführbar. </ListItem><ListItem level="1">Der prolongierten/kontinuierlichen Gabe des Antibiotikums sollte immer eine Bolusgabe vorausgehen. </ListItem><ListItem level="1">Bei Substanzen mit einem hohen Verteilungsvolumen (z.B. Tigecyclin) sollte initial eine höhere Dosis verabreicht werden.</ListItem><ListItem level="1">Mögliche ökonomische Vorteile ergeben sich bei kontinuierlicher Gabe, da bei nicht Schwerkranken mit niedrigeren Tagesdosierungen ähnliche Serumkonzentrationen im Fließgleichgewicht (steady state) wie bei der intermittierenden Gabe erreicht werden können.</ListItem><ListItem level="1">Einige Beta-Lactam-Antibiotika sind wegen der geringen Stabilität bei Raumtemperatur für eine kontinuierliche Gabe nicht geeignet. In diesen Fällen ist nur eine verlängerte Infusionsdauer (3–4 Stunden) möglich.</ListItem><ListItem level="1">Die Empfehlungen der Hersteller zu Art der Lösungsmittel und der Konzentrationen der Antibiotika-Lösungen sind strikt einzuhalten. Abweichungen können erheblich eingeschränkte Stabilität bewirken.</ListItem><ListItem level="1">Bei kontinuierlicher Gabe von Beta-Lactam-Antibiotika ist hierfür ein eigener Zugang oder ein eigenes Lumen erforderlich, da zahlreiche Inkompatibilitätsreaktionen mit anderen Arzneimitteln auftreten.</ListItem><ListItem level="1">Bioverfügbarkeitsdaten der Antibiotika zur Sequenztherapie können Tabelle 5 <ImgLink imgNo="5" imgType="table"/> entnommen werden.</ListItem></UnorderedList></Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Continuous or prolonged infusions of beta-lactam antibiotics"> <MainHeadline>Continuous or prolonged infusions of beta-lactam antibiotics</MainHeadline><Pgraph>Beta-lactam antibiotics are effective if the MIC of the pathogens is exceeded as permanently as possible during the growth phase of the cell wall. Initially, the bactericidal activity increases with increasing concentrations of the antibiotic up to 4 to 5 times the MIC but higher levels will not improve the therapeutic outcome. This pharmacokinetic-pharmacodynamic relationship is described as a time-dependent (non-concentration-dependent) bactericide. For beta-lactam antibiotics, the concentration of unbound antibiotic should exceed the MIC of the pathogen at the site of infection for at least 40–60% of that time <TextLink reference="53"></TextLink>, with approximately 40% for carbapenems and higher for cephalosporins; penicillins are in between. These data are derived from animal studies. Clinical trial results in intensive care patients suggest that keeping above the MIC 100% of the time can improve outcome <TextLink reference="54"></TextLink>, <TextLink reference="55"></TextLink>, <TextLink reference="56"></TextLink>, <TextLink reference="57"></TextLink>, <TextLink reference="58"></TextLink>. Since in intensive care patients with severe infections in deep compartments the plasma concentrations measured in the context of TDM do not correspond to active site concentrations, as a PK/PD target some experts recommend keeping the plasma level 4 to 5 times above the MIC for the full dosing interval <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>. </Pgraph><Pgraph>The pharmacokinetic properties of beta-lactam-antibiotics do not show great variability one from another. Beta-lactam antibiotics are rapidly distributed in the extracellular space after parenteral administration. At steady state, similar concentrations are reached after intermittent administration and bolus administration followed by continuous infusion <TextLink reference="59"></TextLink>, <TextLink reference="60"></TextLink>, <TextLink reference="61"></TextLink>, <TextLink reference="62"></TextLink>, <TextLink reference="63"></TextLink>, <TextLink reference="64"></TextLink>.</Pgraph><Pgraph>The manufacturer’s dosage recommendations usually call for administering beta-lactam antibiotics 2 to 4 times (1 to 6 times) depending on the pharmacokinetic parameters. As a result, approved indications which are confirmed by clinical studies usually result in sufficient free efficacy levels which exceed the MIC of sensitive pathogens. However, intermittent application often fails to achieve the goal of exceeding the pathogen’s MIC permanently at the site of the infection, as shown in PK/PD simulations, experimental and clinical studies <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="10"></TextLink>. This is especially true in patients with high extracellular distribution spaces and an increased clearance rate. In particular this includes patients with a hyperdynamic circulatory situation and a capillary leak, e.g. in sepsis, patients with cystic fibrosis, drainage, bleeding, large burns, ascites, severe pancreatitis, patients with a BMI >30 kg/m<Superscript>2</Superscript>, congestive heart failure, edema, haemofiltration (depending on balance), dialysis patients (pre-dialysis) and pregnant women <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>. In contrast, dehydrated patients, dialysis patients following dialysis and patients under volume restrictions have a lower volume of distribution than normal patients. For high-risk patients and in geriatrics, bespoke antibiotic treatment is therefore required <TextLink reference="4"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="8"></TextLink>, <TextLink reference="65"></TextLink>, <TextLink reference="66"></TextLink>, <TextLink reference="67"></TextLink>, <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink>, <TextLink reference="70"></TextLink>, <TextLink reference="71"></TextLink>, <TextLink reference="72"></TextLink>, <TextLink reference="73"></TextLink>, <TextLink reference="74"></TextLink>, <TextLink reference="75"></TextLink>, <TextLink reference="76"></TextLink>, <TextLink reference="77"></TextLink>.</Pgraph><Pgraph>Recommendations for prolonged administration (over 3–4 hours) or continuous administration of beta-lactam antibiotics are based on theoretical considerations supported by experimental studies or simulations. Clinical examinations show advantages for prolonged or continuous administration with longer-lasting serum levels above the MIC even at lower daily doses <TextLink reference="78"></TextLink>, <TextLink reference="79"></TextLink>, <TextLink reference="80"></TextLink>, <TextLink reference="81"></TextLink>, <TextLink reference="82"></TextLink>, <TextLink reference="83"></TextLink>, <TextLink reference="84"></TextLink>, <TextLink reference="85"></TextLink>, <TextLink reference="86"></TextLink>,<TextLink reference="87"></TextLink>, <TextLink reference="88"></TextLink>, <TextLink reference="89"></TextLink>, <TextLink reference="90"></TextLink>, <TextLink reference="91"></TextLink>, <TextLink reference="92"></TextLink>, <TextLink reference="93"></TextLink>, <TextLink reference="94"></TextLink>, <TextLink reference="95"></TextLink>, <TextLink reference="96"></TextLink> with comparable effectiveness and safety <TextLink reference="71"></TextLink>, <TextLink reference="97"></TextLink>, <TextLink reference="98"></TextLink> in terms of clinical and microbiological efficacy. Advantages of prolonged antibiotic administration have been shown, above all, in severely ill intensive care patients (APACHE II score >17) <TextLink reference="99"></TextLink>. There is currently no agreement regarding the superiority of continuous or intermittent administration <TextLink reference="100"></TextLink>, <TextLink reference="101"></TextLink>, <TextLink reference="102"></TextLink>, <TextLink reference="103"></TextLink>, <TextLink reference="104"></TextLink>. A recent clinical study was not able to objectify differences in mortality <TextLink reference="105"></TextLink>. However, another recent study underlined an improved healing rate following continuous administration <TextLink reference="106"></TextLink>. This result was confirmed again by a recent meta-analysis <TextLink reference="107"></TextLink>. Continuous application of beta-lactam antibiotics without TDM is not recommended without restriction because there is a risk of permanently falling below the pathogen’s MIC. Not only does falling below the MIC result in a lack of efficacy of the antibiotic but it can also favor the selection of resistant mutants. Securely reaching rational PK/PD goals can only be ensured with TDM and it is therefore of crucial importance in continuous application. Against this background prolonged application is much safer.</Pgraph><Pgraph>Beta-lactam antibiotics have limited stability after preparation. It is not only the degree of degradation that is crucial but also the type of decomposition products that have allergenic potential. This fact is insufficiently considered in numerous studies on the stability of the substances. According to these studies, solutions of beta-lactam antibiotics are considered to be stable over a period of time if their degradation level is below 10%. The extent of the degradation depends on the solvent, the effects of light, the concentration of the antibiotic, the type of application aids as well as their production and temperature. In the case of close-fitting pump application in outpatient parenteral antibiotic therapy (OPAT), significant stability losses must be taken into account due to increased ambient heat.</Pgraph><Pgraph>The use of the recommended solvents is of great practical importance to ensure optimum solubility and stability. Almost without exception, all penicillins (dry substances) must be dissolved in aqua ad injectabilia in order to accelerate the dissolution behavior and to ensure particle freedom. Further dilution is then usually possible in conventional infusion solutions. Many beta-lactam antibiotics show a number of incompatibility reactions with other medicines when administered in the same infusion system. The manufacturer’s information on compatibility must be observed.</Pgraph><Pgraph>The most common adverse drug reactions of penicillins are allergies and pseudoallergic reactions. The cause of these reactions is the presence of an unstable beta-lactam structure or specific side chains. Penicillins in solution vary in stability depending on their side chains and the pH. The degradation products of penicillins act as haptens and can form covalent bonds with the body’s own proteins. They form a hapten-protein complex that can induce an allergy-producing immune response. The degradation products of penicillins have a significant potential for allergic reactions. Further information on safety can be found in chapter 4 <TextLink reference="108"></TextLink>.</Pgraph><Pgraph>The nature and extent of the degradation of the beta-lactam antibiotics are substance-dependent. Acylaminopenicillins, isoxazolylpenicillins, cephalosporins and aztreonam are generally more stable than benzylpenicillin because of their structure. Ring-opening, however, is also possible with cephalosporins by nucleophilic or (more rarely) electrophilic attack, as the example of ceftazidime and other cephalosporins shows <TextLink reference="109"></TextLink>. The chemical stability of carbapenems varies widely and above all depends on the concentration of the solution and the temperature <TextLink reference="110"></TextLink>, <TextLink reference="111"></TextLink>. There are very contradictory data for the stability of various beta-lactam antibiotics in infusion solutions. Here the recommendation of the manufacturer of the product should be observed.</Pgraph><Pgraph>Like beta-lactam antibiotics in patients with severe infections, linezolid has a high variability in serum concentrations, with insufficient blood levels under standard dosage regimens. Current data indicate that a continuous application can also make a useful contribution to achieving PK/PD goals <TextLink reference="112"></TextLink>, <TextLink reference="113"></TextLink>.</Pgraph><SubHeadline>Conclusion</SubHeadline><Pgraph><UnorderedList><ListItem level="1">Due to pharmacokinetic/pharmacodynamic considerations, prolonged or continuous infusion of beta-lactam antibiotics is superior to intermittent administration with respect to the therapeutic goal of exceeding the MIC of the pathogens as continually as possible. </ListItem><ListItem level="1">There is some clinical data on the significant superiority of this treatment regimen.</ListItem><ListItem level="1">Continuous and intermittent infusions of a beta-lactam antibiotic show a comparable side effect profile.</ListItem><ListItem level="1">Prolonged/continuous administration is recommended in patients whose pharmacokinetic parameters (volume of distribution, clearance) are significantly different from normal population data (for example, patients with sepsis and septic shock, cystic fibrosis, or patients with severe infections due to pathogens with reduced sensitivity). Continuous application is only recommended under TDM. Prolonged administration of a beta-lactam antibiotic is safe even without TDM. </ListItem><ListItem level="1">Prolonged/continuous administration of the antibiotic should always be preceded by a bolus dose. </ListItem><ListItem level="1">For substances with a high volume of distribution (for example tigecycline), a higher dose should be given initially.</ListItem><ListItem level="1">Possible economic advantages result from continuous administration, since similar serum concentrations in steady state compared to intermittent administration can be achieved with lower daily doses in patients who are not seriously ill.</ListItem><ListItem level="1">Some beta-lactam antibiotics are not suitable for continuous administration due to their low stability at room temperature. In these cases, only a prolonged infusion period (3–4 hours) is possible.</ListItem><ListItem level="1">The manufacturer’s recommendations regarding the type of solvents and the concentrations of the antibiotic solutions must be strictly adhered to. Deviations can result in considerably limited stability.</ListItem><ListItem level="1">Continuous administration of beta-lactam antibiotics requires separate access or lumen, as there are numerous incompatibility reactions with other medicinal products.</ListItem><ListItem level="1">Bioavailability data of the antibiotics for sequential therapy can be found in Table 5 <ImgLink imgNo="5" imgType="table"/>.</ListItem></UnorderedList></Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Arzneimittelinteraktionen"> <MainHeadline>Arzneimittelinteraktionen</MainHeadline><Pgraph>Eine wichtige Ursache für unerwünschte Nebenwirkungen können Interaktionen mit anderen Arzneimitteln sein. Insbesondere die Hemmung hepatischer Monooxygenasen, der Cytochrom-P450-Enzyme, z.B. durch einige Makrolide und Fluorchinolone sowie Azol-Antimykotika, bedingen meist ein höheres Nebenwirkungsrisiko.</Pgraph><Pgraph>Auch eine induktionsverstärkte Expression von Enzymen des Cytochrom-P450-Enzymsystems, z.B. durch Rifampicin, Barbiturate und Carbamazepin ist möglich. Konsequenz ist ein erniedrigter Plasmaspiegel mit reduzierter Wirksamkeit des jeweils betroffenen Pharmakons.</Pgraph><Pgraph>Weitere wichtige Beispiele zu Interaktionen von Antibiotika mit anderen Arzneimitteln sind in Tabelle 6 <ImgLink imgNo="6" imgType="table"/> dargestellt. </Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Drug interactions"> <MainHeadline>Drug interactions</MainHeadline><Pgraph>An important cause of unwanted side effects may be interactions with other drugs. In particular, the inhibition of hepatic monooxygenases, the cytochrome P450 enzymes, usually cause a higher risk of side effects, for example through some macrolides and fluoroquinolones as well as azole antifungals.</Pgraph><Pgraph>Also, induction-enhanced expression of enzymes of the cytochrome P450 enzyme system is possible, for example through rifampicin, barbiturates and carbamazepine. The consequence is a reduced plasma level with reduced effectiveness of the particular drug concerned.</Pgraph><Pgraph>More important examples of interactions of antibiotics with other drugs are presented in Table 6 <ImgLink imgNo="6" imgType="table"/>.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Anmerkung"> <MainHeadline>Anmerkung</MainHeadline><Pgraph>Dies ist das dritte Kapitel der von der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) herausgegebenen S2k Leitlinie „Kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen – Update 2018“ in der 2. aktualisierten Fassung.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Note"> <MainHeadline>Note</MainHeadline><Pgraph>This is the third chapter of the guideline “Calculated initial parenteral treatment of bacterial infections in adults – update 2018” in the 2<Superscript>nd</Superscript> updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für 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 erklären, dass sie keine Interessenkonflikte in Zusammenhang mit diesem Artikel haben.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Competing interests"> <MainHeadline>Competing interests</MainHeadline><Pgraph>The authors declare that they have no competing interests.</Pgraph></TextBlock> <References linked="yes"> <Reference refNo="1"> <RefAuthor>Lee BL</RefAuthor> <RefAuthor>Sachdeva M</RefAuthor> <RefAuthor>Chambers HF</RefAuthor> <RefTitle>Effect of protein binding of daptomycin on MIC and antibacterial activity</RefTitle> <RefYear>1991</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2505-8</RefPage> <RefTotal>Lee BL, Sachdeva M, Chambers HF. Effect of protein binding of daptomycin on MIC and antibacterial activity. 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DOI: 10.3205/id000060</RefTotal> <RefLink>https://doi.org/10.3205/id000060</RefLink> </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: Pharmakokinetische Charakteristika parenteraler Antibiotika</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 1: Pharmacokinetic characteristics of parenteral antibiotics</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>2</MediaNo> <MediaID language="de">2de</MediaID> <MediaID language="en">2en</MediaID> <Caption language="de"><Pgraph><Mark1>Tabelle 2: Kompartimente mit leichter und schwerer Erreichbarkeit für Antibiotika</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 2: Compartments with easy and difficult access for antibiotics</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>3</MediaNo> <MediaID language="de">3de</MediaID> <MediaID language="en">3en</MediaID> <Caption language="de"><Pgraph><Mark1>Tabelle 3: PK/PD Parameter von Antibiotika-Gruppen</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 3: PK/PD parameters of antibiotic groups</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>4</MediaNo> <MediaID language="de">4de</MediaID> <MediaID language="en">4en</MediaID> <Caption language="de"><Pgraph><Mark1>Tabelle 4: Empfohlene Zielbereiche für Tal- und Spitzenspiegel im Rahmen des TDM von Aminoglykosid- und Glykopeptid-Antibiotika (modifiziert nach Burton et al. [15])</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 4: Recommended target ranges for peak and trough levels in the TDM of aminoglycoside and glycopeptide antibiotics (modified according to Burton et al. [15])</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>5</MediaNo> <MediaID language="de">5de</MediaID> <MediaID language="en">5en</MediaID> <Caption language="de"><Pgraph><Mark1>Tabelle 5: Orale Bioverfügbarkeit der Antibiotika zur Sequenztherapie</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 5: Oral bioavailability of antibiotics for sequential therapy</Mark1></Pgraph></Caption> </Table> <Table format="png"> <MediaNo>6</MediaNo> <MediaID language="de">6de</MediaID> <MediaID language="en">6en</MediaID> <Caption language="de"><Pgraph><Mark1>Tabelle 6: Interaktionen von Antibiotika mit anderen Arzneimitteln und deren Folgen</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 6: Interactions of antibiotics with other medicines and their consequences</Mark1></Pgraph></Caption> </Table> <NoOfTables>6</NoOfTables> </Tables> <Figures> <NoOfPictures>0</NoOfPictures> </Figures> <InlineFigures> <NoOfPictures>0</NoOfPictures> </InlineFigures> <Attachments> <NoOfAttachments>0</NoOfAttachments> </Attachments> </Media> </OrigData> </GmsArticle>