Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Infektionen durch multiresistente gramnegative Stäbchen – ESBL-Bildner, Carbapenemase-bildende Enterobacteriaceae, Carbapenem-resistente Acinetobacter baumannii

id000048 10.3205/id000048 urn:nbn:de:0183-id0000485 Leitlinie Guideline Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Infektionen durch multiresistente gramnegative Stäbchen – ESBL-Bildner, Carbapenemase-bildende Enterobacteriaceae, Carbapenem-resistente Acinetobacter baumannii Calculated parenteral initial treatment of bacterial infections: Infections with multi-resistant Gram-negative rods – ESBL producers, carbapenemase-producing Enterobacteriaceae, carbapenem-resistant Acinetobacter baumannii Grabein Grabein Béatrice B Dr.

Stabsstelle Klinische Mikrobiologie und Krankenhaushygiene, Klinikum der Universität München, Campus Großhadern, Marchioninistraße 17, 81377 München, DeutschlandStabsstelle Klinische Mikrobiologie und Krankenhaushygiene, Klinikum der Universität München, München, Deutschland

Stabsstelle Klinische Mikrobiologie und Krankenhaushygiene, Klinikum der Universität München, Campus Großhadern, Marchioninistraße 17, 81377 München, GermanyStabsstelle Klinische Mikrobiologie und Krankenhaushygiene, Klinikum der Universität München, Munich, Germany

beatrice.grabein@med.uni-muenchen.de author Ebenhoch Ebenhoch Michael M

Stabsstelle Hygiene, Klinische Infektiologie und Mikrobiologie, BG-Unfallklinik Murnau, DeutschlandStabsstelle Hygiene, Klinische Infektiologie und Mikrobiologie, BG-Unfallklinik Murnau, Deutschland

Stabsstelle Hygiene, Klinische Infektiologie und Mikrobiologie, BG-Unfallklinik Murnau, GermanyStabsstelle Hygiene, Klinische Infektiologie und Mikrobiologie, BG-Unfallklinik Murnau, Germany

author Kühnen Kühnen Ernst E

Mikrobiologie & Hygiene, MVZ Synlab Trier, DeutschlandMikrobiologie & Hygiene, MVZ Synlab Trier, Deutschland

Mikrobiologie & Hygiene, MVZ Synlab Trier, GermanyMikrobiologie & Hygiene, MVZ Synlab Trier, Germany

author Thalhammer Thalhammer Florian F

Klinische Abteilung für Infektiologie und Tropenmedizin, Medizinische Universität Wien, ÖsterreichKlinische Abteilung für Infektiologie und Tropenmedizin, Medizinische Universität Wien, Österreich

Klinische Abteilung für Infektiologie und Tropenmedizin, Medizinische Universität Wien, Vienna, AustriaKlinische Abteilung für Infektiologie und Tropenmedizin, Medizinische Universität Wien, Vienna, Austria

author German Medical Science GMS Publishing House

Düsseldorf

610 Calculated parenteral initial therapy Kalkulierte parenterale Initialtherapie 20200326 germ engl This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). 2195-8831 8 GMS Infectious Diseases GMS Infect Dis 04 Dies ist das sechzehnte 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.Infektionen durch resistente gramnegative Erreger sind eine Herausforderung. In diesem Kapitel werden Therapieempfehlungen für die gezielte Therapie von Infektionen durch ESBL-bildende Enterobacteriaceae, Carbapenemase-bildende Enterobactaeriaceae und Carbapenem-resistente Acinetobacter baumannii gegeben, die auf der begrenzten verfügbaren Evidenz beruhen. This is the sixteenth 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.Infections due to multiresistant Gram-negative rods are challenging. In this chapter recommendations for targeted therapy for infections caused by ESBL-producing Enterobacteriaceae, carbapenemase-producing Enterobacteriaceae and carbapenem-resistant Acinetobacter baumannii are given, based on the limited available evidence. Antibiotika zur Therapie von Infektionen durch MRGNAmoxicillin/Clavulansäure und Piperacillin/TazobactamDefinitionsgemäß hemmt Clavulansäure in vitro ESBL-positive Enterobakterien und hat im Vergleich zu Sulbactam eine höhere Beta-Lactamase-Inhibitor (BLI) Aktivität . Tazobactam besitzt eine stärkere inhibitorische Aktivität als Clavulansäure und Sulbactam gegen ESBL, zeigt jedoch fast immer eine unzureichende inhibitorische Aktivität gegen Carbapenemasen . Rezente Studien zeigen, dass bei gegebener In-vitro-Empfindlichkeit Amoxicillin/Clavulansäure bzw. Piperacillin/Tazobactam zur Therapie von Infektionen durch ESBL-bildende Enterobacteriaceae eingesetzt werden können , . Hierbei muss jedoch ein Inokulum-Effekt berücksichtigt werden, welcher bei Piperacillin/Tazobactam ausgeprägter als bei Amoxicillin/Clavulansäure ist , , . Als logische Konsequenz wurden in den aktuellen EUCAST-Richtlinien separate Grenzwerte für Amoxicillin/Clavulansäure für Urinisol</PlainText></TextGroup>ate von <Mark2>Escherichia coli</Mark2> eingeführt <TextLink reference="8"></TextLink>. Außerdem ist zu berücksichtigen, dass in unterschiedlichen Ländern und Regionen unterschiedliche ESBL-Typen vorhanden sind. Die klinischen Daten beziehen sich überwiegend auf Typen, die in Spanien und Italien weit verbreitet sind. Inwieweit diese Daten auf deutsche oder österreichische Verhältnisse übertragbar sind, ist derzeit nicht eindeutig geklärt.</Pgraph><SubHeadline>Temocillin</SubHeadline><Pgraph>Temocillin, 1988 eingeführt, ist ein semisynthetisches <TextGroup><PlainText>6-α</PlainText></TextGroup>-Methoxyderivat von Ticarcillin, welches gegen zahlreiche Enterobakterien wirksam ist, jedoch nicht gegen Non-Fermenter, grampositive Aerobier und Anaerobier. Die Methoxygruppe bewirkt, dass Temocillin gegen zahlreiche Beta-Lactamasen <TextLink reference="9"></TextLink>, inklusive ESBL <TextLink reference="10"></TextLink>, <TextLink reference="11"></TextLink>, AmpC <TextLink reference="12"></TextLink> und gegen <Mark2>Klebsiella-pneumoniae</Mark2>-Carbapenemasen (KPC), jedoch nicht gegen Metallo-Beta-Lactamasen und OXA-48 stabil ist. Die Standarddosierung beträgt 2x 2 g und die zugelassene maximale Dosierung 3x 2 g Temocillin. Eine kürzlich publizierte Studie empfiehlt für kritisch kranke Patienten eine Tagesdosis von 6 g Temocillin, entweder dreimal täglich intermittierend oder nach einer Ladungsdosis von 2 g Temocillin kontinuierlich <TextLink reference="13"></TextLink>. Eine englische Studie mit einem breiten Indikationsspektrum (Harnwegsinfektion, Bakteriämie, Pneumonie) bestätigt die Wirksamkeit von Temocillin bei ESBL- bzw. AmpC-positiven Enterobakterien-Infektionen <TextLink reference="14"></TextLink>. Temocillin ist in Belgien, Frankreich und Großbritannien, jedoch nicht in Deutschland, Österreich und der Schweiz zugelassen. In begründeten Fällen ist die Einzeleinfuhr nach §73 Abs.3 AMG aber möglich.</Pgraph><Pgraph> </Pgraph><SubHeadline>Avibactam</SubHeadline><Pgraph>Avibactam ist der erste Vertreter einer neuen Klasse von Nicht-Beta-Lactam-Beta-Lactamase-Inhibitoren. Diese BLI sind potenter und breiter wirksam als Tazobactam. Sie schließen auch Beta-Lactamasen der Ambler Klassen A (inklusive Carbapenemasen wie KPC), C (AmpC) sowie D ein (Tabelle 1 <ImgLink imgNo="1" imgType="table"/>) <TextLink reference="15"></TextLink>, <TextLink reference="16"></TextLink>. Avibactam ist in der Kombination mit Ceftazidim bereits zugelassen und wird in der Kombination mit Ceftarolin bzw. Aztreonam in Studien z.Zt. geprüft.</Pgraph><SubHeadline>Ceftazidim/Avibactam</SubHeadline><Pgraph>Die fixe Kombination Ceftazidim/Avibactam hat aufgrund der oben erwähnten Beta-Lactamase-Aktivität gegen AmpC-Beta-Lactamasen auch eine etwa vierfach stärkere Wirkung gegen <Mark2>Pseudomonas aeruginosa</Mark2> als Ceftazidim alleine <TextLink reference="17"></TextLink>. Bedingt durch den Austausch einer Aminosäure in der Carbapenemase KPC-2 wurden bei <Mark2>Escherichia coli</Mark2> bereits Resistenzen gegen Ceftazidim/Avibactam beobachtet <TextLink reference="3"></TextLink>. Die empfohlene Dosierung ist 3x 2,5 g Ceftazidim/Avibactam entsprechend einem Verhältnis von 2 g Ceftazidim zu 0,5 g Avibactam. Es liegen auch Phase-1-Studiendaten zu 3x 4 g Ceftazidim/Avibactam (3 g + 1 g) vor <TextLink reference="18"></TextLink>. Die Elimination der beiden Arzneistoffe erfolgt ausschließlich renal, weshalb entsprechende Dosisanpassungen bei eingeschränkter Nierenfunktion notwendig sind. Die Konzentration beider Substanzen in der Epithelial lining Flüssigkeit (ELF) betrug etwa 30% der Plasmakonzentration. Die Zulassung erfolgte für komplizierte intraabdominelle Infektionen, komplizierte Harnwegsinfektionen einschließlich Pyelonephritis, nosokomiale Pneumonie, einschließlich beatmungsassoziierter Pneumonie, sowie für die Behandlung von Infektionen aufgrund aerober gramnegativer Erreger bei erwachsenen Patienten mit begrenzten Behandlungsoptionen. </Pgraph><SubHeadline>Ceftolozan/Tazobactam</SubHeadline><Pgraph>Ceftolozan ist dem Ceftazidim strukturell ähnlich, unterscheidet sich jedoch von Ceftazidim durch die Seitenkette an Position 3 <TextLink reference="19"></TextLink>. Hieraus resultiert eine starke Bindung an die Penicillin-bindenden Proteine, welche für die hohe Aktivität gegen <Mark2>Pseudomonas aeruginosa</Mark2>, einschließlich mehrfach resistenter Stämme, verantwortlich ist <TextLink reference="20"></TextLink>. Die fixe Kombination ist zudem wirksam gegen ESBL-po<TextGroup><PlainText>s</PlainText></TextGroup>itive Enterobakterien, jedoch nicht gegen AmpC- und Carbapenemase-bildende Stämme (Tabelle 2 <ImgLink imgNo="2" imgType="table"/>) <TextLink reference="21"></TextLink>, <TextLink reference="22"></TextLink>. Ceftolozan/Tazobactam ist für die Behandlung intraabdomineller Infektionen (in Kombination mit Metronidazol) <TextLink reference="23"></TextLink> sowie komplizierter Harnwegsinfektionen und der Pyelonephritis <TextLink reference="24"></TextLink> zugelassen. Die zugelassene Dosierung von Ceftolozan/Tazobactam (in einem Verhältnis von 2:1) beträgt 3x 1,5 g bei einer Infusionsdauer über eine Stunde, für die Behandlung der Pneumonie wird eine Dosierung von 3x 3 g in der Zulassungsstudie verwendet (<Hyperlink href="https://clinicaltrials.gov/ct2/show/NCT02070757">https://clinicaltrials.gov/ct2/show/NCT02070757</Hyperlink>).</Pgraph><SubHeadline>Ertapenem</SubHeadline><Pgraph>Ertapenem ist ein Carbapenem ohne Aktivität gegen Non-Fermenter und Enterokokken. Im Gegensatz zur US-amerikanischen Zulassung ist Ertapenem in Europa nur für die Therapie von intraabdominellen Infektionen, ambulant erworbenen Pneumonien, akuten gynäkologischen Infektionen sowie Haut- und Weichgewebeinfektionen beim diabetischen Fußsyndrom zugelassen, jedoch nicht für Harnwegsinfektionen und Pyelonephritis, obgleich es hierfür gute Studiendaten gibt <TextLink reference="25"></TextLink>. Ertapenem ist wie alle Carbapeneme gegen ESBL-positive Enterobakterien aktiv. Die Dosierung beträgt aufgrund der langen Halbwertszeit 1x 1 g Ertapenem, wobei zur Behandlung der nicht urogenitalen Infektionen wegen der hohen Eiweißbindung die zulassungsüberschreitende Dosierung (Off-Label-Use) von 1x 2 g Ertapenem empfohlen wird <TextLink reference="26"></TextLink>. Vorsicht ist bei Patienten mit eingeschränkter Nierenfunktion geboten, da bei diesen durch höhere Plasmaspiegel klassentypische ZNS-Nebenwirkungen auftreten können.</Pgraph><SubHeadline>Tigecyclin</SubHeadline><Pgraph>Tigecyclin, eine Weiterentwicklung von Minocyclin, ist der erste Vertreter der Glycylcycline mit einem breiten Wirkspektrum, welches MRSA, VRE und ESBL-bildende Enterobacteriaceae einschließt. <Mark2>Pseudomonas aeruginosa</Mark2> wird hingegen nicht erfasst, im Gegenteil sogar selektioniert. </Pgraph><Pgraph>Aufgrund der sehr guten Membrangängigkeit und des damit verbundenen hohen Verteilungsvolumens erreicht Tigecyclin nur sehr geringe Serumkonzentration. Damit ist die Substanz nur bedingt zur Therapie von bakteriämisch verlaufenden Infektionen geeignet <TextLink reference="27"></TextLink>. In klinischen Studien zeigte sich eine signifikante Unterlegenheit im Vergleich zu Imipenem bei der Behandlung von Patienten mit einer <Mark2>Acinetobacter-baumannii</Mark2>-Bakteriämie <TextLink reference="28"></TextLink>. Auch in der Behandlung von Patienten mit nosokomialer, beatmungsassoziierter Pneumonie war Tigecyclin dem Imipenem signifikant unterlegen <TextLink reference="29"></TextLink>, <TextLink reference="30"></TextLink>. Die Ursache hierfür dürfte ein zu niedriges Verhältnis AUC/MHK aufgrund der nur mäßigen Lungenpenetration gewesen sein. In einer Phase-II-Studie wurde Tigecyclin bei Patienten mit nosokomialer Pneumonie in höherer Dosierung eingesetzt. Der klinische Heilungserfolg war in der Gruppe der Patienten, die 200 mg als Anfangsdosis und danach 100 mg alle 12 h erhielten, höher als in der Gruppe der mit Imipenem behandelten Patienten und der Gruppe, die Tigecyclin in einer niedrigeren Dosierung (150 mg als Anfangsdosis, danach 75 mg alle 12 h) erhielten <TextLink reference="31"></TextLink>. Deshalb sollte Tigecyclin bei schweren Infektionen in der beschriebenen höheren Dosierung eingesetzt werden <TextLink reference="31"></TextLink>.</Pgraph><SubHeadline>Fosfomycin</SubHeadline><Pgraph>Fosfomycin sollte zur Vermeidung des Risikos einer Resistenzentwicklung unter Therapie immer nur im Rahmen einer Kombinationstherapie und im Hinblick auf das PK/PD-Verhältnis in hoher Dosierung (bis 24 g Fosfomycin/Tag, siehe Tabelle 2 <ImgLink imgNo="2" imgType="table"/> und Tabelle 3 <ImgLink imgNo="3" imgType="table"/>) verabreicht werden <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>. Fosfomycin weist zahlreiche positive Eigenschaften wie fehlende Proteinbindung, hohe Wirkspiegel sowie sehr gute Penetration in Muskel, Lunge, Knochen, Liquor <TextLink reference="34"></TextLink> und Biofilme sowie Schutz vor Ototoxizität und Nephrotoxizität <TextLink reference="35"></TextLink> auf. Als negativ sind die hohe Natriumbelastung (14,5 mval Na+ pro g) und die verstärkte Kaliumsekretion zu werten. </Pgraph><Pgraph>Eine frühe Metaanalyse untersuchte die Wirksamkeit von Fosfomycin bei ESBL-positiven Stämmen von <Mark2>Escherichia coli</Mark2> bzw. <Mark2>Klebsiella pneumoniae</Mark2> und schlussfolgert, dass Fosfomycin bei Harnwegsinfektionen eingesetzt werden kann <TextLink reference="36"></TextLink>. Eine im selben Jahr publizierte spanische Studie berichtete allerdings, dass mit zunehmender Zahl der Fosfomycin-Verordnungen ein Anstieg der Resistenzrate bei den ESBL-positiven <Mark2>Escherichia-coli</Mark2>-Stämmen gegenüber Fosfomycin von 4,4% (2005) auf 11,4% (2009) verbunden war <TextLink reference="37"></TextLink>. </Pgraph><SubHeadline>Colistin</SubHeadline><Pgraph>Bei den Dosisangaben ist zu beachten, dass 30 mg Colistin-Base 1 Mio. IE entsprechen. </Pgraph><Pgraph>Colistin ist sowohl gegenüber ESBL-bildenden Enterobacteriaceae als auch gegenüber Carbapenemase-bildenden Enterobacteriaceae in vitro wirksam. Colistin wirkt ebenfalls gegenüber Carbapenem-resistenten <Mark2>Acinetobacter-baumannii</Mark2>-Stämmen und gegenüber multiresistenten <Mark2>Pseudomonas-aeruginosa</Mark2>-Isolaten.</Pgraph><Pgraph>Colistin ist angezeigt zur Behandlung der folgenden Infektionen: Beatmungsassoziierte Pneumonie, Bakteriämie/Sepsis, Abdominal-, Harnwegs- und Knocheninfekte sowie Meningitis <TextLink reference="38"></TextLink>. Die initiale i.v. Ladungsdosis soll bei 9–12 Mio. IE liegen <TextLink reference="39"></TextLink>, da ausreichend hohe Wirkspiegel sonst erst nach 2–3 Tagen erreicht werden. Höhere Erhaltungsdosen werden unter Beachtung von Körpergewicht, Kreatinin-Clearance und Neurotoxizität meist gut toleriert <TextLink reference="39"></TextLink>, <TextLink reference="40"></TextLink>.</Pgraph><Pgraph>Zusätzlich zur systemischen Gabe besteht die Möglichkeit der inhalativen Gabe zur Behandlung der Pneumonie. Es werden damit deutlich höhere Konzentrationen im Sputum <TextLink reference="41"></TextLink> und im Lungengewebe <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink> erreicht als bei der intravenösen Applikation. Die zusätzliche inhalative Therapie führte zur schnelleren mikrobiologischen Eradikation und zu höheren klinischen Heilungsraten. Allerdings ließ sich in den bisherigen klinischen Studien keine Senkung der Letalität nachweisen <TextLink reference="44"></TextLink>, <TextLink reference="45"></TextLink>. Die Applikation sollte über einen Ultraschallvernebler mit einer anzustrebenden Partikelgröße von 3–5 µm erfolgen <TextLink reference="46"></TextLink>. </Pgraph><Pgraph>Aufgrund der sehr schlechten Penetration von Polymyxinen in das ZNS bei intravenöser Gabe kann Colistin bei Patienten mit ZNS-Infektionen intraventrikulär bzw. intrathekal verabreicht werden. </Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Antibiotics for the treatment of infections with MRGN"> <MainHeadline>Antibiotics for the treatment of infections with MRGN</MainHeadline><SubHeadline>Amoxicillin/clavulanic acid and piperacillin/tazobactam</SubHeadline><Pgraph>By definition, clavulanic acid inhibits ESBL-positive enterobacteria in vitro and has higher beta-lactamase inhibitor (BLI) activity compared to sulbactam <TextLink reference="1"></TextLink>. Tazobactam has a stronger inhibitory activity than clavulanic acid and sulbactam against ESBL but almost always exhibits inadequate inhibitory activity against carbapenemases <TextLink reference="2"></TextLink>. Recent studies show that amoxicillin/clavulanic acid or piperacillin/tazobactam can be used to treat infections with ESBL-producing Enterobacteriaceae which have shown sensitivity in vitro <TextLink reference="3"></TextLink>, <TextLink reference="4"></TextLink>. However, an inoculum effect must be taken into account, which is more pronounced in piperacillin/tazobactam than in amoxicillin/clavulanic acid <TextLink reference="5"></TextLink>, <TextLink reference="6"></TextLink>, <TextLink reference="7"></TextLink>. As a logical consequence, separate limits for amoxycillin/clavulanic acid for urinary isolates of <Mark2>Escherichia</Mark2> <Mark2>coli</Mark2> have been introduced in the current EUCAST guidelines <TextLink reference="8"></TextLink>. It should also be noted that different ESBL types exist in different countries and regions. The clinical data mainly refer to types that are widespread in Spain and Italy. The extent to which these data can be transferred to current conditions in Germany or Austria is not clear.</Pgraph><SubHeadline>Temocillin</SubHeadline><Pgraph>Temocillin, introduced in 1988, is a semisynthetic 6-α-methoxy derivative of ticarcillin which is active against many enterobacteria but not against non-fermenters, Gram-positive aerobes and anaerobes. The methoxy group causes temocillin to target numerous beta-lactamases <TextLink reference="9"></TextLink>, including ESBL <TextLink reference="10"></TextLink>, <TextLink reference="11"></TextLink>, AmpC <TextLink reference="12"></TextLink> and <Mark2>Klebsiella</Mark2> <Mark2>pneumoniae</Mark2> carbapenemases (KPC) but is not stable against metallo-beta-lactamases and OXA-48. The standard dosage is 2x 2 g and the maximum permissible dosage 3x 2 g temocillin. A recently published study recommends a daily dose of 6 g of temocillin for critically ill patients either intermittently three times a day or continuously after a loading dose of 2 g of temocillin <TextLink reference="13"></TextLink>. An English study with a broad range of indications (urinary tract infection, bacteraemia, pneumonia) confirms the efficacy of temocillin in ESBL- and AmpC-positive enterobacterial infections <TextLink reference="14"></TextLink>. Temocillin is approved in Belgium, France and the UK but not in Germany, Austria and Switzerland. In justified cases, individual import is possible according to §73 Sect. 3 Medicinal Products Act.</Pgraph><SubHeadline>Avibactam</SubHeadline><Pgraph>Avibactam is the first member of a new class of non-beta-lactam beta-lactamase inhibitors. These BLIs are more potent and broader acting than tazobactam. They also include Ambler class A beta-lactamases (including carbapenemases such as KPC), C (AmpC), and D (Table 1 <ImgLink imgNo="1" imgType="table"/>) <TextLink reference="15"></TextLink>, <TextLink reference="16"></TextLink>. Avibactam is already approved in combination with ceftazidime and, used in combination with ceftaroline or aztreonam, is currently being checked in studies.</Pgraph><SubHeadline>Ceftazidime/avibactam</SubHeadline><Pgraph>The fixed combination ceftazidime/avibactam also has an approximately four times stronger effect on <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2> than ceftazidime alone due to the above-mentioned beta-lactamase activity against AmpC-beta-lactamases <TextLink reference="17"></TextLink>. Due to the replacement of an amino acid in the carbapenemase KPC-2, resistance to ceftazidime/avibactam has already been observed in <Mark2>Escherichia coli</Mark2> <TextLink reference="3"></TextLink>. The recommended dosage is <TextGroup><PlainText>3x 2.5 g</PlainText></TextGroup> ceftazidime/avibactam corresponding to a ratio of 2 g ceftazidime to 0.5 g avibactam. There are also phase 1 study data on 3x 4 g ceftazidime/avibactam (3 g + 1 g) <TextLink reference="18"></TextLink>. The elimination of both drugs is exclusively renal, which is why appropriate dose adjustments in cases of renal impairment are necessary. The concentration of both substances in the epithelial lining fluid (ELF) was about 30% of the plasma concentration. Approval has been granted for complicated intra-abdominal infections, complicated urinary tract infections including pyelonephritis, nosocomial pneumonia, including ventilator-associated pneumonia and treatment of infections with aerobic Gram-negative pathogens in adult patients with limited treatment options. </Pgraph><SubHeadline>Ceftolozane/tazobactam</SubHeadline><Pgraph>Ceftolozane is structurally similar to ceftazidime but differs from ceftazidime in the side chain at position 3 <TextLink reference="19"></TextLink>. This results in a strong binding to the penicillin-binding proteins, which are responsible for the high activity against <Mark2>Pseudomonas aeruginosa</Mark2>, including multiply re<TextGroup><PlainText>sistan</PlainText></TextGroup>t strains <TextLink reference="20"></TextLink>. The fixed combination is also effective against ESBL-positive enterobacteria but not against AmpC and carbapenemase-producing strains (Table 2 <ImgLink imgNo="2" imgType="table"/>) <TextLink reference="21"></TextLink>, <TextLink reference="22"></TextLink>. Ceftolozane/tazobactam is approved for the treatment of intra-abdominal infections (in combination with metronidazole) <TextLink reference="23"></TextLink> as well as complicated urinary tract infections and pyelonephritis <TextLink reference="24"></TextLink>. The approved dose of ceftolozane/tazobactam (in a ratio of 2:1) is <TextGroup><PlainText>3x 1.5 g</PlainText></TextGroup> for an infusion period of more than 1 hour, for treatment of pneumonia a dosage of 3x 3 g is used in the approval study (<Hyperlink href="https://clinicaltrials.gov/ct2/show/NCT02070757">https://clinicaltrials.gov/ct2/show/NCT02070757</Hyperlink>).</Pgraph><SubHeadline>Ertapenem</SubHeadline><Pgraph>Ertapenem is a carbapenem with no activity against non-fermenters and enterococci. In contrast to the US approval, ertapenem is only approved in Europe for the treatment of intra-abdominal infections, community-acquired pneumonia, acute gynecological infections and cutaneous and soft tissue infections in diabetic foot syndrome but not for urinary tract infections and pyelonephritis, although good data are available <TextLink reference="25"></TextLink>. Ertapenem, like all carbapenems, is active against ESBL-positive enterobacteria. Due to the long half-life, the dosage is 1x 1 g of ertapenem, whereas for the treatment of non-urogenital infections the off-label use of 1x 2 g of ertapenem is recommended because of the high protein binding <TextLink reference="26"></TextLink>. Caution is advised in patients with impaired renal function, as they may experience class-typical CNS effects due to higher plasma levels.</Pgraph><SubHeadline>Tigecycline</SubHeadline><Pgraph>Tigecycline, an advanced form of minocycline, is the first broad-spectrum glycylcycline which is also effective against MRSA, VRE and ESBL-producing Enterobacteriaceae. However <Mark2>Pseudomonas</Mark2> <Mark2>aeruginosa</Mark2> is not only unaffected but even selected. </Pgraph><Pgraph>Due to the excellent membrane permeability and the associated high volume of distribution, tigecycline only achieves very low serum concentration. Thus the substance is only partly suitable for the treatment of bacteremic infections <TextLink reference="27"></TextLink>. In clinical trials it was significantly inferior to imipenem in the treatment of patients with <Mark2>Acinetobacter baumannii</Mark2> bacteremia <TextLink reference="28"></TextLink>. Tigecycline was also significantly inferior to imipenem in the treatment of patients with nosocomial, ventilator-as<TextGroup><PlainText>sociat</PlainText></TextGroup>ed pneumonia <TextLink reference="29"></TextLink>, <TextLink reference="30"></TextLink>. The reason for this may have been an excessively low AUC/MIC ratio due to only moderate pulmonary penetration. In a Phase II trial, tigecycline was used in higher doses in patients with nosocomial pneumonia. Clinical cure success was higher in the group of patients receiving 200 mg as the initial dose and <TextGroup><PlainText>100 mg</PlainText></TextGroup> every 12 hrs thereafter than in the group of patients treated with imipenem and the lower-dose tigecycline group (150 mg as the starting dose, thereafter <TextGroup><PlainText>75 mg</PlainText></TextGroup> every 12 hrs) <TextLink reference="31"></TextLink>. Therefore, in severe infections, tigecycline should be used at the higher dose described <TextLink reference="31"></TextLink>.</Pgraph><SubHeadline>Fosfomycin</SubHeadline><Pgraph>Fosfomycin should only be given in combination treatment and, with regard to the PK/PD ratio, in high doses (up to 24 g fosfomycin/day, see Table 2 <ImgLink imgNo="2" imgType="table"/> and Table 3 <ImgLink imgNo="3" imgType="table"/>) in order to avoid the risk of developing resistance during treatment <TextLink reference="32"></TextLink>, <TextLink reference="33"></TextLink>. Fosfomycin has numerous benefits such as lack of protein binding, high levels of activity and very good penetration into muscle, lungs, bones, cerebrospinal fluid <TextLink reference="34"></TextLink> and biofilms as well as protection against ototoxicity and nephrotoxicity <TextLink reference="35"></TextLink>. The high sodium load (14.5 m Na<Superscript>+</Superscript> per g) and the increased potassium secretion are negative aspects. </Pgraph><Pgraph>An early meta-analysis examined the efficacy of fosfomycin in ESBL-positive strains of <Mark2>Escherichia coli</Mark2> and <Mark2>Klebsiella pneumoniae</Mark2> respectively and concluded that fosfomycin may be used in urinary tract infections <TextLink reference="36"></TextLink>. However, a Spanish study published in the same year reported that increasing numbers of fosfomycin prescriptions were connected to an increase in the rate of ESBL-positive <Mark2>Escherichia coli</Mark2> strains resistant to fosfomycin from 4.4% (2005) to 11.4% (2009) <TextLink reference="37"></TextLink>. </Pgraph><SubHeadline>Colistin</SubHeadline><Pgraph>Regarding dosages, it should be noted that 30 mg colistin base corresponds to 1 million IU. Colistin is active against both ESBL-producing Enterobacteriaceae and carbapenemase-producing Enterobacteriaceae in vitro. Colistin is also active against carbapenem-resistant <Mark2>Acinetobacter baumannii</Mark2> strains and against multidrug-resistant <Mark2>Pseudomonas aeruginosa</Mark2> isolates.</Pgraph><Pgraph>Colistin is indicated for the treatment of the following infections: ventilator-associated pneumonia, bacteremia/sepsis, abdominal, urinary tract and bone infections as well as meningitis <TextLink reference="38"></TextLink>. The initial i.v. loading dose should be 9–12 million IU <TextLink reference="39"></TextLink>, since otherwise sufficiently high levels of effectiveness can only be achieved after <TextGroup><PlainText>2–3 days</PlainText></TextGroup>. Higher maintenance doses are usually well tolerated taking into account body weight, creatinine clearance and neurotoxicity <TextLink reference="39"></TextLink>, <TextLink reference="40"></TextLink>.</Pgraph><Pgraph>In addition to systemic administration, there is the option of inhaled administration for the treatment of pneumonia. Significantly higher concentrations are achieved in sputum <TextLink reference="41"></TextLink> and lung tissue <TextLink reference="42"></TextLink>, <TextLink reference="43"></TextLink> compared to intravenous administration. Inhalation therapy as an addition resulted in faster microbiological eradication and higher clinical healing rates. However, no reduction in lethality has been demonstrated in clinical studies to date <TextLink reference="44"></TextLink>, <TextLink reference="45"></TextLink>. Application should be carried out using an ultrasonic nebulizer with a particle size of 3–5 µm <TextLink reference="46"></TextLink>. </Pgraph><Pgraph>Due to the very poor penetration of polymyxins into the CNS when given intravenously, colistin can be administered intraventricularly or intrathecally in patients with CNS infections. </Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Therapie von Infektionen durch Extended-Spektrum-Beta-Lactamase-bildende Enterobacteriaceae"> <MainHeadline>Therapie von Infektionen durch Extended-Spektrum-Beta-Lactamase-bildende Enterobacteriaceae</MainHeadline><Pgraph>„Extended-Spektrum“ Beta-Lactamase (ESBL; Beta-Lactamasen mit erweitertem Wirkspektrum) produzierende Enterobakterien haben in den letzten Jahren massiv an Bedeutung gewonnen und stellen heute in Europa ein größeres therapeutisches Problem als Methicillin-resistente <Mark2>Staphylococcus-aureus</Mark2>-Stämme dar <TextLink reference="47"></TextLink>. Die Beta-Lactamasen können gemäß Ambler-Klassifikation in vier Klassen (A–D, Abbildung 1 <ImgLink imgNo="1" imgType="figure"/>) <TextLink reference="48"></TextLink> sowie nach Bush-Jacoby phänotypisch bzw. funktional in drei Gruppen unterteilt werden. Klasse A und D Enzyme hydrolysieren Penicilline sowie – im geringeren Ausmaß – Oxyimino-Cephalosporine; Klasse C Beta-Lactamasen hydrolysieren Cephalospo<TextGroup><PlainText>r</PlainText></TextGroup>ine stärker als Penicilline <TextLink reference="49"></TextLink>. Das Wissen um die einzelnen Beta-Lactamasen ist angesichts der neuen Therapieoptionen notwendig, um die neuen Cephalosporin-Kombinationen punktgenau einsetzen und Carbapeneme in der Therapie von ESBL-positiven Enterobakterien einsparen zu können; diese sind häufig auch gegen Fluorchinolone resistent.</Pgraph><Pgraph>Als Therapieoptionen stehen derzeit Beta-Lactamase-Inhibitoren (Avibactam, Clavulansäure, Tazobactam) in fixer Kombination mit einem Penicillin (Amoxicillin/Clavulansäure, Piperacillin/Tazobactam) oder Cephalosporin (Ceftazidim/Avibactam, Ceftolozan/Tazobactam) sowie Temocillin, die Carbapeneme (Ertapenem, Imipenem/Cilastatin, Meropenem), Colistin, Fosfomycin und Tigecyclin zur Verfügung. </Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Treatment of infections with extended spectrum beta-lactamase-producing Enterobacteriaceae"> <MainHeadline>Treatment of infections with extended spectrum beta-lactamase-producing Enterobacteriaceae</MainHeadline><Pgraph>Extended-spectrum beta-lactamase producing enterobacteria have become increasingly important in recent years and present a major therapeutic problem in Europe today compared to methicillin-resistant <Mark2>Staphylococcus aureus</Mark2> strains <TextLink reference="47"></TextLink>. The beta-lactamases can be divided phenotypically into four classes according to the Ambler classification (A–D, Figure 1 <ImgLink imgNo="1" imgType="figure"/>) <TextLink reference="48"></TextLink> or functionally into three groups according to Bush-Jacoby. Class A and D enzymes hydrolyze penicillins and, to a lesser extent, oxyimino-cephalosporins; class C beta-lactamases hydrolyze cephalosporins more than penicillins <TextLink reference="49"></TextLink>. Awareness of the individual beta-lactamases is necessary in view of the new treatment options in order to apply the new cephalosporin combinations precisely and to save carbapenems in the treatment of ESBL-positive enterobacteria; these are often resistant to fluoroquinolones.</Pgraph><Pgraph>Treatment options currently include beta-lactamase inhibitors (avibactam, clavulanic acid, tazobactam) in fixed combination with penicillin (amoxicillin/clavulanic acid, piperacillin/tazobactam) or cephalosporin (ceftazidime/avibactam, ceftolozane/tazobactam) as well as temocillin, carbapenems (ertapenem, imipenem/cilastatin, meropenem), colistin, fosfomycin, and tigecycline. </Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Therapie von Infektionen durch Carbapenemase-bildende Enterobacteriaceae"> <MainHeadline>Therapie von Infektionen durch Carbapenemase-bildende Enterobacteriaceae</MainHeadline><Pgraph>Die Therapie von Infektionen durch Carbapenemase-bil<TextGroup><PlainText>d</PlainText></TextGroup>ende Enterobacteriaceae, vor allem <Mark2>Klebsiella pneumoniae</Mark2>, aber auch <Mark2>Escherichia coli</Mark2> und andere Vertreter, sogenannte 4MRGN, ist gekennzeichnet durch extrem limitierte Therapieoptionen und das Fehlen prospektiver, randomisierter multizentrischer Studien. Zwei prospektive randomisierte Studien untersuchen derzeit Colistin in Monotherapie versus Colistin in Kombination mit einem Carbapenem (NCT01732250 und NCT01597973). Die Ergebnisse der Studien standen zum Zeitpunkt der Veröffentlichung der vorliegenden Empfehlungen noch nicht zur Verfügung <TextLink reference="50"></TextLink>. Die derzeitigen Therapieempfehlungen basieren demnach im Wesentlichen auf Fallse<TextGroup><PlainText>r</PlainText></TextGroup>ien, Beobachtungsstudien, nicht randomisierten Vergleichsstudien und Expertenmeinungen und konzentrieren sich auf Infektionen durch <Mark2>Klebsiella pneumoniae</Mark2>, meist mit <Mark2>Klebsiella-pneumoniae</Mark2>-Carbapenemasen (KPC), <TextGroup><PlainText>OXA-48</PlainText></TextGroup> oder Metallo-Beta-Lactamasen (z.B. VIM). Ob die Ergebnisse auch auf andere Enterobacteriaceae mit Carbapenem-Resistenz und andere Mechanismen der Carbapenem-Resistenz zu übertragen sind, ist derzeit unklar. </Pgraph><Pgraph>Die Prävalenz Carbapenem-resistenter Klebsiellen steigt auch in Deutschland langsam an, ist aber nach wie vor sehr gering. Das Antibiotika-Resistenz-Surveillance-Sy<TextGroup><PlainText>stem (A</PlainText></TextGroup>RS) am RKI weist für das Jahr 2015 eine Prävalenz von 0,4% Carbapenem-intermediären und <TextGroup><PlainText>-res</PlainText></TextGroup>istenten Stämmen bezogen auf Imipenem und <TextGroup><PlainText>Meropenem</PlainText></TextGroup> aus (<Hyperlink href="https://ars.rki.de/Content/Database/ResistanceDevelopment.aspx">https://ars.rki.de/Content/Database/ResistanceDevelopment.aspx</Hyperlink>). In der PEG Resistenzstudie 2013 betrug der Anteil der nicht mehr voll empfindlichen Stämme 1,6% (Imipenem) bzw. 1,3% (Meropenem) <TextGroup><PlainText>(</PlainText><Hyperlink href="https://www.p-e-g.org/resistenzdaten.html">https://www.p-e-g.org/resistenzdaten.html</Hyperlink><PlainText>)</PlainText></TextGroup>. Die Daten des Nationalen Referenzzentrums für gramnegative Erreger zeigen, dass in Deutschland vor allem OXA-48 gefunden wird, daneben KPC-2, VIM-1, NDM-1 und KPC-3 <TextLink reference="51"></TextLink>.</Pgraph><Pgraph>Als in vitro wirksame Therapieoptionen stehen prinzipiell Colistin, Tigecyclin, einige Aminoglykoside und Fosfomycin zur Verfügung. Auch Ceftazidim/Avibactam ist gegenüber KPC-Bildnern in vitro wirksam. Der Stellenwert von Ceftazidim/Avibactam als Möglichkeit zur Behandlung von Infektionen durch KPC-Bildner ist aufgrund der limitierten klinischen Daten derzeit aber noch nicht abzuschätzen.</Pgraph><Pgraph>Der Nachweis einer Carbapenemase als Resistenzmechanismus führt nicht immer zu einem phänotypisch resistenten Erreger. Daher spielt die Kenntnis über die minimale Hemmkonzentration (MHK) des Erregers eine wesentliche Rolle, weshalb mikrobiologische Laboratorien bei Carbapenemase-Bildnern unbedingt die MHK für Imipenem und/oder Meropenem berichten sollten. Die MHK für Ertapenem ist zwar der beste Marker für das Vorliegen einer Carbapenemase, sie spielt jedoch für die Frage einer Option für eine Kombinationstherapie eine untergeordnete Rolle. Für MHK-Werte bis 8 mg/l gegenüber Meropenem wird eine Wirksamkeit als Kombinationspartner postuliert.</Pgraph><Pgraph>Die bisher vorliegenden klinischen Daten, die allerdings aus nicht randomisierten Studien mit kleinen Fallzahlen stammen, deuten darauf hin, dass bei Infektionen durch Carbapenem-resistente Enterobacteriaceae vorzugsweise eine Kombinationstherapie unter Einschluss eines Carbapenems eingesetzt werden sollte <TextLink reference="52"></TextLink>, <TextLink reference="53"></TextLink>, <TextLink reference="54"></TextLink>. Allerdings ist die Datenlage durch viele ungeklärte Fragen gekennzeichnet. In einer Fallserie aus Griechenland <TextLink reference="52"></TextLink> waren viele Isolate phänotypisch nicht Carbapenem-re<TextGroup><PlainText>sis</PlainText></TextGroup>tent, außerdem werden meist keine Angaben gemacht, ob bei den Patienten eine Monoinfektion durch den Carbapenem-resistenten Stamm oder eine polymikrobielle Infektion unter Beteiligung auch von Carbapenem-emp<TextGroup><PlainText>f</PlainText></TextGroup>indlichen Isolaten vorlag. Dies würde einen Bias zugunsten der Kombination bedingen, da die Carbapenem-sensiblen Erreger mit einem wirksamen Therapiere<TextGroup><PlainText>g</PlainText></TextGroup>ime behandelt wurden <TextLink reference="55"></TextLink>. In den meisten Studien fand auch keine Adjustierung statt, ob die kalkulierte Initialthe<TextGroup><PlainText>ra</PlainText></TextGroup>pie adäquat oder inadäquat war. Als weiterer kritischer Punkt ist zu sehen, dass die Dosierungsempfehlungen für Colistin erst kürzlich deutlich erhöht wurden. In den „Kombinationstherapie-Studien“ wurde vielfach keine nach heutigen Gesichtspunkten ausreichend hohe Dosierung verabreicht. </Pgraph><Pgraph>Ein Therapieansatz mit zwei Carbapenemen – Ertapenem plus Doripenem oder Meropenem – ist theoretisch attraktiv <TextLink reference="56"></TextLink>. Das Prinzip beruht darauf, dass die Carbapenemasen eine höhere Affinität zu Ertapenem als zu Doripenem und Meropenem haben. Wird Ertapenem (eine Stunde) vor Doripenem bzw. Meropenem verabreicht, wird Ertapenem zwar inaktiviert, bleibt aber an der Carbapenemase gebunden, sodass das andere Carbapenem (Doripenem oder Meropenem) wirken kann <TextLink reference="56"></TextLink>. Bisher wurden 38 Fälle von Patienten, die dieses Therapieregime erhielten, publiziert. Bei 22 Patienten war die Therapie erfolgreich <TextLink reference="56"></TextLink>, <TextLink reference="57"></TextLink>, <TextLink reference="58"></TextLink>, <TextLink reference="59"></TextLink>.</Pgraph><Pgraph>Zur Bedeutung von Fosfomycin als Kombinationspartner liegt eine multizentrische prospektive Beobachtungsstudie mit 41 Intensiv-Patienten vor. In allen Fällen war eine Blutstrominfektion oder Beatmungs-assoziierte Pneumonie durch einen Carbapenem-resistenten <Mark2>Klebsiella</Mark2>-<Mark2>pneumoniae</Mark2>-Stamm diagnostiziert worden. Die Therapie führte bei Gabe einer medianen Dosis von 24 g/Tag bei etwa 54% der Patienten zum klinischen Erfolg. Die Kombinationspartner waren überwiegend Tigecyclin und Colistin, aber auch Carbapeneme und Aminoglykoside <TextLink reference="60"></TextLink>.</Pgraph><Pgraph>Bisher gibt es keine Daten zu einer geeigneten Antibiotika-Kombination, die im Sinne eines „Carbapenem-sparenden“ Regimes oder in Situationen, wo aufgrund der Höhe der MHK kein Carbapenem eingesetzt werden kann, verwendet werden soll. Unklar ist auch, ob eine Kombination aus drei in vitro wirksamen Antibiotika einer Kombination aus zwei in vitro wirksamen Antibiotika überlegen ist, auch wenn die Daten aus einigen Fallserien vorsichtig in diese Richtung interpretiert werden könnten. </Pgraph><SubHeadline>Therapieempfehlung</SubHeadline><Pgraph>Trotz der geringen Evidenz wird auf der Basis der vorliegenden Daten eine Therapieempfehlung durch die Expertengruppe ausgesprochen, die bis zum Vorliegen der Ergebnisse von randomisierten klinischen Studien als Basis für die Behandlung der Patienten mit schweren Infektionen durch Carbapenem-resistente Enterobacteriaceae dienen soll.</Pgraph><Pgraph>Bei schweren Infektionen, wie Blutstrominfektionen oder Pneumonie, wird eine Kombinationstherapie empfohlen. Wenn die Carbapenem-MHK bei 8 mg/l oder darunter liegt, ist eine Carbapenem-basierte Kombinationstherapie zu bevorzugen. Liegt die Carbapenem-MHK über 8 mg/l, sollte eine Kombination aus Colistin und Tigecyclin und ggf. zusätzlich Fosfomycin oder ein Aminoglykosid gegeben werden.</Pgraph><Pgraph>Die prolongierte oder kontinuierliche Gabe von Carbapenemen zur Behandlung von Infektionen durch Carbapenem-resistente Enterobacteriaceae ist bisher nicht untersucht worden. Daher wird hier keine Empfehlung für oder gegen diese Applikationsformen ausgesprochen. Die kontinuierliche Gabe des Carbapenems soll aber auf keinen Fall ohne ein therapeutisches Drug-Monitoring erfolgen, da die Gefahr kontinuierlich subtherapeutischer Spiegel besteht (s.a. Kapitel 3 <TextLink reference="61"></TextLink> und Kapitel 11 <TextLink reference="62"></TextLink>). </Pgraph><Pgraph>Colistin erreicht bei systemischer Gabe nur niedrige Konzentrationen im Lungengewebe, so dass eine additive inhalative Therapie bei Pneumonie erwogen werden kann <TextLink reference="63"></TextLink>.</Pgraph><Pgraph>Tabelle 3 <ImgLink imgNo="3" imgType="table"/> macht Vorschläge für die Therapie bei Pneumonie und Sepsis durch Carbapenem-resistente Enterobacteriaceae.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Treatment of infections with carbapenemase-producing Enterobacteriaceae"> <MainHeadline>Treatment of infections with carbapenemase-producing Enterobacteriaceae</MainHeadline><Pgraph>The treatment of infections with carbapenemase-pro<TextGroup><PlainText>duc</PlainText></TextGroup>ing Enterobacteriaceae, especially <Mark2>Klebsiella pneumoniae</Mark2> but also <Mark2>Escherichia coli</Mark2> and other representatives, so-called 4MRGN, is characterized by extremely limited treatment options and the absence of prospective randomized multicenter studies. Two prospective randomized studies are currently investigating colistin in monotherapy versus colistin in combination with a carbapenem (NCT01732250 and NCT01597973). The results of these studies were not available at the time of publication of these recommendations <TextLink reference="50"></TextLink>. Therefore the current treatment recommendations are based essentially on case series, observational studies, non-randomized comparative studies and expert opinions and focus on infections with <Mark2>Klebsiella pneumoniae</Mark2>, usually with <Mark2>Klebsiella</Mark2> <Mark2>pneumoniae</Mark2> carbapenemases (KPC), OXA-48 or metallo-beta-lactamases (for example VIM). Whether the results are transferable to other Enterobacteriaceae with carbapenem resistance and other mechanisms of carbapenem resistance is currently unclear. </Pgraph><Pgraph>The prevalence of carbapenem-resistant Klebsiella is also increasing slowly in Germany but is still very low. The <TextGroup><PlainText>Antibiotic</PlainText></TextGroup> Resistance Surveillance System (ARS) at the RKI reports a prevalence of 0.4% carbapenem-interme<TextGroup><PlainText>dia</PlainText></TextGroup>te and -resistant strains for imipenem and meropenem in 2015 (<Hyperlink href="https://ars.rki.de/Content/Database/ResistanceDevelopment.aspx">https://ars.rki.de/Content/Database/ResistanceDevelopment.aspx</Hyperlink>). In the 2013 PEG Resistance Study, the proportion of strains that were no longer sensitive was 1.6% (imipenem) and 1.3% (meropenem) (<Hyperlink href="https://www.p-e-g.org/resistenzdaten.html">https://www.p-e-g.org/resistenzdaten.html</Hyperlink>). Data from the National Reference Center for Gram-negative Pathogens show that OXA-48 is found in Germany, as well as KPC-2, VIM-1, NDM-1 and KPC-3 <TextLink reference="51"></TextLink>.</Pgraph><Pgraph>In principle, colistin, tigecycline, some aminoglycosides and fosfomycin are available as treatment options effective in vitro. Ceftazidime/avibactam is also active against KPC-producers in vitro. However, the status of ceftazidime/avibactam as a potential treatment option for infections with KPC producers can currently not be assessed due to limited clinical data.</Pgraph><Pgraph>The detection of a carbapenemase as a resistance mechanism does not always lead to a phenotypically resistant pathogen. Therefore knowledge of the minimum inhibitory concentration (MIC) of the pathogen is essential and the reason why microbiological laboratories should definitely report the MIC for imipenem and/or meropenem in carbapenemase producers. While the MIC for ertapenem is the best marker for the presence of carbapenemase, it plays a minor role in deciding options for combination therapy. Compared to meropenem, efficacy as a combination partner is postulated for MIC values up to 8 mg/l.</Pgraph><Pgraph>However, clinical data available to date from non-randomized small case studies indicate that combination treatment involving carbapenem should be preferred for infections with carbapenem-resistant Enterobacteriaceae <TextLink reference="52"></TextLink>, <TextLink reference="53"></TextLink>, <TextLink reference="54"></TextLink>. However, there are many unanswered questions regarding the data. In a case series from Greece <TextLink reference="52"></TextLink> many isolates were phenotypically non-carbapenem-resistant and, in most cases, no information was provided whether the patients had mono-infection by the carbapenem-resistant strain or polymicrobial infection involving carbapenem-sensitive isolates. This would create a bias in favor of the combination as the carbapenem-sensitive pathogens were treated with an effective treatment regimen <TextLink reference="55"></TextLink>. In most studies, no adjustment was made as to whether the calculated initial treatment was adequate or inadequate. Another critical point is that the dose recommendations for colistin have recently been increased significantly. In the “Combination Therapy Studies”, the dosages administered were not sufficiently high according to today’s standards. </Pgraph><Pgraph>A therapeutic approach with two carbapenems – ertapenem plus doripenem or meropenem – is theoretically attractive <TextLink reference="56"></TextLink>. The principle is based on the fact that the carbapenemases have a higher affinity for ertapenem than for doripenem and meropenem. When ertapenem is given (1 hour) before doripenem or meropenem, ertapenem is inactivated but remains bound to the carbapenemase, so that the other carbapenem (doripenem or meropenem) may act <TextLink reference="56"></TextLink>. To date, 38 cases of patients receiving this treatment regimen have been published. In 22 patients treatment was successful <TextLink reference="56"></TextLink>, <TextLink reference="57"></TextLink>, <TextLink reference="58"></TextLink>, <TextLink reference="59"></TextLink>.</Pgraph><Pgraph>A multi-center prospective observational study with <TextGroup><PlainText>41 i</PlainText></TextGroup>ntensive care patients is available on the importance of fosfomycin as a combination partner. In all cases, a bloodstream infection or ventilator-associated pneumonia with a carbapenem-resistant <Mark2>Klebsiella pneumoniae</Mark2> strain had been diagnosed. Treatment led to clinical success in approximately 54% of patients given a median dose of 24 g/day. The combination partners were predominantly tigecycline and colistin but also carbapenems and aminoglycosides <TextLink reference="60"></TextLink>.</Pgraph><Pgraph>To date there is no data available on a suitable combination of antibiotics to be used as a “carbapenem-sparing” regimen or in situations where carbapenem cannot be used because of the level of MICs. It is also unclear whether a combination of three in vitro antibiotics is superior to a combination of two in vitro antibiotics, although the data from some case series could be cautiously interpreted in this direction. </Pgraph><SubHeadline>Recommended treatment</SubHeadline><Pgraph>On the basis of the available data, despite the low level of evidence, a recommendation for treatment was issued by the expert group, which should serve as the basis for the treatment of patients with severe infections with carbapenem-resistant Enterobacteriaceae until the results of randomized clinical studies are available.</Pgraph><Pgraph>Combination treatment is recommended for severe infections such as bloodstream infections or pneumonia. If carbapenem MIC is at or below 8 mg/l, carbapenem-based combination treatment is preferable. If the carbapenem MIC is above 8 mg/l, a combination of colistin and tigecycline and, if appropriate, fosfomycin or an aminoglycoside should be given.</Pgraph><Pgraph>Prolonged or continuous administration of carbapenems for the treatment of infections by carbapenem-resistant Enterobacteriaceae has not been studied to date. Therefore, no recommendation is made here for or against these forms of application. However, continuous administration of a carbapenem should never take place without therapeutic drug monitoring, since there is a risk of continuous sub-therapeutic levels (see also chapter 3 <TextLink reference="61"></TextLink> and chapter 11 <TextLink reference="62"></TextLink>). </Pgraph><Pgraph>Colistin achieves only low concentrations in the lung tissue when administered systemically, so that inhalation therapy as an addition can be considered in pneumonia <TextLink reference="63"></TextLink>.</Pgraph><Pgraph>Table 3 <ImgLink imgNo="3" imgType="table"/> provides suggestions for the treatment of pneumonia and sepsis by carbapenem-resistant Enterobacteriaceae.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Therapie von Infektionen durch Carbapenem-resistente Acinetobacter-baumannii-Stämme"> <MainHeadline>Therapie von Infektionen durch Carbapenem-resistente Acinetobacter-baumannii-Stämme</MainHeadline><Pgraph>Die Therapie von Infektionen durch Carbapenem-resiste<TextGroup><PlainText>n</PlainText></TextGroup>te <Mark2>Acinetobacter-baumannii</Mark2>-Stämme, sogenannten 4MRGN, stellt eine große Herausforderung dar. In diesen Fällen stehen nur noch wenige wirksame Antibiotika zu Verfügung, für die es allesamt keine groß angelegten prospektiven Studien zur klinischen Wirksamkeit gibt, so dass die Therapieempfehlungen auf Fallserien, nicht randomisierten Vergleichsstudien und Expertenmeinungen beruhen.</Pgraph><Pgraph>Neben Colistin und Tigecyclin sind bei <Mark2>Acinetobacter-baumannii</Mark2>-Infektionen Sulbactam und Cotrimoxazol von Bedeutung. Colistin sollte in Kombination mit einer zweiten wirksamen Substanz, wie z.B. Tigecyclin, Sulbactam, einem Aminoglykosid oder auch einem Carbapenem, kombiniert werden, da kleinere Beobachtungsstudien Hinweise liefern konnten, dass eine Kombinationstherapie einer Monotherapie mit Colistin überlegen ist <TextLink reference="64"></TextLink>.</Pgraph><SubHeadline>Sulbactam</SubHeadline><Pgraph>Sulbactam hat eine hohe Affinität zu den Penicillin-bin<TextGroup><PlainText>d</PlainText></TextGroup>enden Proteinen 1a und 2 und besitzt daher als einziger synthetischer Beta-Lactamase-Inhibitor eine relevante antibakterielle Aktivität gegen <Mark2>Acinetobacter baumannii</Mark2>. Die Substanz ist charakterisiert durch eine zeitabhängige Bakterizidie, welche am besten über die %T>MHK beschrieben wird <TextLink reference="65"></TextLink>, <TextLink reference="66"></TextLink>. Im Tiermodell zeigte die Therapie mit Sulbactam vergleichbare Ergebnisse wie Imipenem, aber höhere Heilungs- und Überlebensraten als Colistin <TextLink reference="67"></TextLink>. Die wenigen klinischen Daten, die zur Verfügung stehen, weisen aus, dass die Therapie mit Sulbactam ebenso effektiv ist wie die Therapie mit einem Carbapenem bzw. Colistin <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink>, <TextLink reference="70"></TextLink>. In einer weiteren Arbeit fanden sich sogar signifikant höhere klinische Heilungsraten für Sulbactam im Vergleich zu Colistin <TextLink reference="71"></TextLink>.</Pgraph><SubHeadline>Cotrimoxazol (Trimethoprim/Sulfamethoxazol)</SubHeadline><Pgraph>Cotrimoxazol zeigt eine hohe In-vitro-Wirksamkeit, auch bei Colistin-resistenten Stämmen <TextLink reference="72"></TextLink>, <TextLink reference="73"></TextLink>. Von den im Jahr 2015 in Deutschland im Rahmen von ARS getesteten <Mark2>Acinetobacter-baumannii</Mark2>-Komplex-Isolaten waren 92,1% Cotrimoxazol-sensibel <TextLink reference="74"></TextLink>. Vergleichbare Daten konnten in den PEG-Resistenzstudien 2010 und 2013 mit Sensibilitätsraten von 74,7% bzw. 71,6% für <Mark2>Acinetobacter baumannii</Mark2> sensu stricto gezeigt werden <TextLink reference="75"></TextLink>. Allerdings gibt es keine klinische Studie zur Wirksamkeit. Es existieren lediglich Fallberichte, wo Cotrimoxazol meist in Kombination mit einer zweiten Substanz gegeben wurde. Alle veröffentlichten Fälle einer Therapie mit Cotrimoxazol wurden als Therapieerfolg beschrieben <TextLink reference="76"></TextLink>. Eine generelle Therapieempfehlung kann mangels Daten aber nicht gegeben werden. Allerdings steht mit Cotrimoxazol eine Substanz zur Verfügung, die insbesondere bei Infektionen durch Colistin-resistente Stämme eine mögliche Therapieoption, speziell bei Harnwegsinfektionen, darstellt.</Pgraph><SubHeadline>Kombinationstherapie</SubHeadline><Pgraph>Aufgrund der suboptimalen Pharmakokinetik und schnellen Resistenzentwicklung, sowohl von Colistin als auch von Tigecyclin, und der eingeschränkten Vorhersagbarkeit des Ergebnisses der In-vitro-Testung von Sulbactam auf die klinische Wirksamkeit wurden in mehreren Studien verschiedene Kombinationstherapien untersucht. In einer retrospektiven Arbeit bei Patienten mit <Mark2>Acineto</Mark2><Mark2></Mark2><TextGroup><Mark2>bacter-baumannii</Mark2></TextGroup>-Bakteriämien war die Kombination aus Colistin, entweder mit einem Carbapenem, Sulbactam oder bei wenigen Patienten mit einem anderem Kombinationspartner, der Monotherapie mit Colistin bezüglich der Letalität signifikant überlegen <TextLink reference="64"></TextLink>. Carbapeneme scheinen auch bei In-vitro-Resistenz klinisch eine synergistische Wirkung in Kombination mit Colistin zu entwickeln. </Pgraph><Pgraph>Rifampicin zeigt in vitro eine hohe Aktivität gegen multiresistente <Mark2>Acinetobacter-baumannii</Mark2>-Stämme. Im Tierexperiment konnte eine Überlegenheit der Kombination aus Rifampicin mit Colistin im Vergleich zu Colistin alleine demonstriert werden <TextLink reference="64"></TextLink>. Allerdings ließ sich dieser Effekt in zwei prospektiven klinischen Studien nicht bestätigen <TextLink reference="77"></TextLink>, <TextLink reference="78"></TextLink>. Deshalb kann aufgrund des hohen Interaktionspotentiales und der Hepatotoxizität im Moment eine Kombinationstherapie mit Rifampicin nicht empfohlen werden <TextLink reference="79"></TextLink>.</Pgraph><Pgraph>Tabelle 4 <ImgLink imgNo="4" imgType="table"/> und Tabelle 5 <ImgLink imgNo="5" imgType="table"/> fassen die Vorschläge für die Therapie von Infektionen durch Carbapenem-resistente <Mark2>Acinetobacter baumannii</Mark2> zusammen.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Treatment of infections with carbapenem-resistant Acinetobacter baumannii strains"> <MainHeadline>Treatment of infections with carbapenem-resistant Acinetobacter baumannii strains</MainHeadline><Pgraph>The treatment of infections with carbapenem-resistant <Mark2>Acinetobacter baumannii</Mark2> strains, so-called 4MRGN, presents a great challenge. In these cases, only a few effective antibiotics are available and for which there are no large-scale prospective studies on clinical efficacy. So the treatment recommendations are based on case series, non-randomized comparative studies and expert opinions.</Pgraph><Pgraph>Apart from colistin and tigecycline, sulbactam and cotrimoxazole are important in <Mark2>Acinetobacter baumannii</Mark2> infections.</Pgraph><Pgraph>Colistin should be used in combination with a second active substance, for example tigecycline, sulbactam, an aminoglycoside or even a carbapenem because smaller observational studies have provided evidence that combination treatment is superior to monotherapy with colistin <TextLink reference="64"></TextLink>.</Pgraph><SubHeadline>Sulbactam</SubHeadline><Pgraph>Sulbactam has a high affinity for the penicillin-binding proteins 1a and 2 and therefore as the only synthetic beta-lactamase inhibitor has relevant antibacterial activity against <Mark2>Acinetobacter baumannii</Mark2>. The substance is characterized as a time-dependent bactericide, which is best described by the %T >MIC <TextLink reference="65"></TextLink>, <TextLink reference="66"></TextLink>. In animal experiments treatment with sulbactam showed results comparable to imipenem but higher healing and survival rates compared to colistin <TextLink reference="67"></TextLink>. The few clinical data available indicate that treatment with sulbactam is as effective as treatment with a carbapenem or colistin <TextLink reference="68"></TextLink>, <TextLink reference="69"></TextLink>, <TextLink reference="70"></TextLink>. Another study even found significantly higher clinical healing rates for sulbactam compared to colistin <TextLink reference="71"></TextLink>.</Pgraph><SubHeadline>Cotrimoxazole (trimethoprim/sulfamethoxazole)</SubHeadline><Pgraph>Cotrimoxazole shows high in vitro efficacy, even in colistin-resistant strains <TextLink reference="72"></TextLink>, <TextLink reference="73"></TextLink>. 92.1% of the <Mark2>Acinetobacter baumannii</Mark2> complex isolates tested by ARS in Germany in 2015 were cotrimoxazole-sensitive <TextLink reference="74"></TextLink>. Comparable data were found in the PEG resistance studies in 2010 and 2013 with sensitivity rates of 74.7% and 71.6% respectively for <Mark2>Acinetobacter baumannii</Mark2> sensu stricto, <TextLink reference="75"></TextLink>. However, there is no clinical study on efficacy. There are only case reports where cotrimoxazole was usually given in combination with a second substance. All published cases of treatment with cotrimoxazole have been described as a therapeutic success <TextLink reference="76"></TextLink>. A general treatment recommendation cannot be given for lack of data. However, cotrimoxazole remains a possible treatment option, especially for infections caused by colistin-resistant strains and particularly in urinary tract infections.</Pgraph><SubHeadline>Combination treatment</SubHeadline><Pgraph>Several combination treatments were investigated in multiple studies due to the sub-optimal pharmacokinetics and rapid development of resistance both to colistin and tigecycline and the limited predictability of the results of in vitro testing of sulbactam on clinical efficacy. In a retrospective study of patients with <Mark2>Acinetobacter baumannii</Mark2> bacteremia, the combination of colistin either with a carbapenem, sulbactam or in a few patients with another combination partner, was significantly superior to colistin monotherapy as regards mortality <TextLink reference="64"></TextLink>. Carbapenems appear to be clinically synergistic in combination with colistin even with in vitro resistance. </Pgraph><Pgraph>Rifampicin shows high activity in vitro against multidrug-resistant <Mark2>Acinetobacter baumannii</Mark2> strains. In animal experiments, a superiority of the combination of rifampicin with colistin was demonstrated in comparison to colistin alone <TextLink reference="64"></TextLink>. However, this effect could not be confirmed in two prospective clinical studies <TextLink reference="77"></TextLink>, <TextLink reference="78"></TextLink>. Therefore, combination treatment with rifampicin is currently not recommended due to the high potential for interaction and hepatotoxicity <TextLink reference="79"></TextLink>.</Pgraph><Pgraph>Table 4 <ImgLink imgNo="4" imgType="table"/> and Table 5 <ImgLink imgNo="5" imgType="table"/> summarize the proposals for the treatment of infections with carbapenem-resistant <Mark2>Acinetobacter baumannii</Mark2>.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Anmerkung"> <MainHeadline>Anmerkung</MainHeadline><Pgraph>Dies ist das sechzehnte 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 sixteenth chapter of the guideline “Calculated initial parenteral treatment of bacterial infections in adults – update 2018” in the 2<Superscript>nd</Superscript> updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemothe<TextGroup><PlainText>ra</PlainText></TextGroup>pie e.V. (PEG) has been translated to address an international audience.</Pgraph></TextBlock> <TextBlock language="de" linked="yes" name="Interessenkonflikte"> <MainHeadline>Interessenkonflikte</MainHeadline><Pgraph>Die Autoren erklären, dass sie keine Interessenkonflikte in Zusammenhang mit diesem Artikel haben.</Pgraph></TextBlock> <TextBlock language="en" linked="yes" name="Competing interests"> <MainHeadline>Competing interests</MainHeadline><Pgraph>The authors declare that they have no competing interests.</Pgraph></TextBlock> <References linked="yes"> <Reference refNo="1"> <RefAuthor>Payne DJ</RefAuthor> <RefAuthor>Cramp R</RefAuthor> <RefAuthor>Winstanley DJ</RefAuthor> <RefAuthor>Knowles DJ</RefAuthor> <RefTitle>Comparative activities of clavulanic acid, sulbactam, and tazobactam against clinically important beta-lactamases</RefTitle> <RefYear>1994</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>767-72</RefPage> <RefTotal>Payne DJ, Cramp R, Winstanley DJ, Knowles DJ. Comparative activities of clavulanic acid, sulbactam, and tazobactam against clinically important beta-lactamases. Antimicrob Agents Chemother. 1994 Apr;38(4):767-72. DOI: 10.1128/AAC.38.4.767</RefTotal> <RefLink>https://doi.org/10.1128/AAC.38.4.767</RefLink> </Reference> <Reference refNo="2"> <RefAuthor>Drawz SM</RefAuthor> <RefAuthor>Bonomo RA</RefAuthor> <RefTitle>Three decades of beta-lactamase inhibitors</RefTitle> <RefYear>2010</RefYear> <RefJournal>Clin Microbiol Rev</RefJournal> <RefPage>160-201</RefPage> <RefTotal>Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010 Jan;23(1):160-201. DOI: 10.1128/CMR.00037-09</RefTotal> <RefLink>https://doi.org/10.1128/CMR.00037-09</RefLink> </Reference> <Reference refNo="3"> <RefAuthor>Rodríguez-Baño J</RefAuthor> <RefAuthor>Picón E</RefAuthor> <RefAuthor>Gijón P</RefAuthor> <RefAuthor>Hernández JR</RefAuthor> <RefAuthor>Ruíz M</RefAuthor> <RefAuthor>Peña C</RefAuthor> <RefAuthor>Almela M</RefAuthor> <RefAuthor>Almirante B</RefAuthor> <RefAuthor>Grill F</RefAuthor> <RefAuthor>Colomina J</RefAuthor> <RefAuthor>Giménez M</RefAuthor> <RefAuthor>Oliver A</RefAuthor> <RefAuthor>Horcajada JP</RefAuthor> <RefAuthor>Navarro G</RefAuthor> <RefAuthor>Coloma A</RefAuthor> <RefAuthor>Pascual A</RefAuthor> <RefAuthor> Spanish Network for Research in Infectious Diseases (REIPI)</RefAuthor> <RefTitle>Community-onset bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: risk factors and prognosis</RefTitle> <RefYear>2010</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>40-8</RefPage> <RefTotal>Rodríguez-Baño J, Picón E, Gijón P, Hernández JR, Ruíz M, Peña C, Almela M, Almirante B, Grill F, Colomina J, Giménez M, Oliver A, Horcajada JP, Navarro G, Coloma A, Pascual A; Spanish Network for Research in Infectious Diseases (REIPI). Community-onset bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: risk factors and prognosis. Clin Infect Dis. 2010 Jan;50(1):40-8. DOI: 10.1086/649537</RefTotal> <RefLink>https://doi.org/10.1086/649537</RefLink> </Reference> <Reference refNo="4"> <RefAuthor>Rodríguez-Baño J</RefAuthor> <RefAuthor>Navarro MD</RefAuthor> <RefAuthor>Retamar P</RefAuthor> <RefAuthor>Picón E</RefAuthor> <RefAuthor>Pascual Á</RefAuthor> <RefAuthor> Extended-Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria Group</RefAuthor> <RefTitle>β-Lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts</RefTitle> <RefYear>2012</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>167-74</RefPage> <RefTotal>Rodríguez-Baño J, Navarro MD, Retamar P, Picón E, Pascual Á; Extended-Spectrum Beta-Lactamases–Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria Group. β-Lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis. 2012 Jan;54(2):167-74. DOI: 10.1093/cid/cir790</RefTotal> <RefLink>https://doi.org/10.1093/cid/cir790</RefLink> </Reference> <Reference refNo="5"> <RefAuthor>Thomson KS</RefAuthor> <RefAuthor>Moland ES</RefAuthor> <RefTitle>Cefepime, piperacillin-tazobactam, and the inoculum effect in tests with extended-spectrum beta-lactamase-producing Enterobacteriaceae</RefTitle> <RefYear>2001</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>3548-54</RefPage> <RefTotal>Thomson KS, Moland ES. Cefepime, piperacillin-tazobactam, and the inoculum effect in tests with extended-spectrum beta-lactamase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2001 Dec;45(12):3548-54. DOI: 10.1128/AAC.45.12.3548-3554.2001</RefTotal> <RefLink>https://doi.org/10.1128/AAC.45.12.3548-3554.2001</RefLink> </Reference> <Reference refNo="6"> <RefAuthor>Harris PN</RefAuthor> <RefAuthor>Tambyah PA</RefAuthor> <RefAuthor>Paterson DL</RefAuthor> <RefTitle>β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options?</RefTitle> <RefYear>2015</RefYear> <RefJournal>Lancet Infect Dis</RefJournal> <RefPage>475-85</RefPage> <RefTotal>Harris PN, Tambyah PA, Paterson DL. β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options? Lancet Infect Dis. 2015 Apr;15(4):475-85. DOI: 10.1016/S1473-3099(14)70950-8</RefTotal> <RefLink>https://doi.org/10.1016/S1473-3099(14)70950-8</RefLink> </Reference> <Reference refNo="7"> <RefAuthor>López-Cerero L</RefAuthor> <RefAuthor>Picón E</RefAuthor> <RefAuthor>Morillo C</RefAuthor> <RefAuthor>Hernández JR</RefAuthor> <RefAuthor>Docobo F</RefAuthor> <RefAuthor>Pachón J</RefAuthor> <RefAuthor>Rodríguez-Baño J</RefAuthor> <RefAuthor>Pascual A</RefAuthor> <RefTitle>Comparative assessment of inoculum effects on the antimicrobial activity of amoxycillin-clavulanate and piperacillin-tazobactam with extended-spectrum beta-lactamase-producing and extended-spectrum beta-lactamase-non-producing Escherichia coli isolates</RefTitle> <RefYear>2010</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>132-6</RefPage> <RefTotal>López-Cerero L, Picón E, Morillo C, Hernández JR, Docobo F, Pachón J, Rodríguez-Baño J, Pascual A. Comparative assessment of inoculum effects on the antimicrobial activity of amoxycillin-clavulanate and piperacillin-tazobactam with extended-spectrum beta-lactamase-producing and extended-spectrum beta-lactamase-non-producing Escherichia coli isolates. Clin Microbiol Infect. 2010 Feb;16(2):132-6. DOI: 10.1111/j.1469-0691.2009.02893.x</RefTotal> <RefLink>https://doi.org/10.1111/j.1469-0691.2009.02893.x</RefLink> </Reference> <Reference refNo="8"> <RefAuthor>The European Committee on Antimicrobial Susceptibility Testing</RefAuthor> <RefTitle></RefTitle> <RefYear>2017</RefYear> <RefBookTitle>Breakpoint tables for interpretation of MICs and zone diameters. Version 7-1</RefBookTitle> <RefPage></RefPage> <RefTotal>The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 7-1. 2017. Available from: http://www.eucast.org/ast_of_bacteria/previous_versions_of_documents/</RefTotal> <RefLink>http://www.eucast.org/ast_of_bacteria/previous_versions_of_documents/</RefLink> </Reference> <Reference refNo="9"> <RefAuthor>Matagne A</RefAuthor> <RefAuthor>Lamotte-Brasseur J</RefAuthor> <RefAuthor>Dive G</RefAuthor> <RefAuthor>Knox JR</RefAuthor> <RefAuthor>Frère JM</RefAuthor> <RefTitle>Interactions between active-site-serine beta-lactamases and compounds bearing a methoxy side chain on the alpha-face of the beta-lactam ring: kinetic and molecular modelling studies</RefTitle> <RefYear>1993</RefYear> <RefJournal>Biochem J</RefJournal> <RefPage>607-11</RefPage> <RefTotal>Matagne A, Lamotte-Brasseur J, Dive G, Knox JR, Frère JM. Interactions between active-site-serine beta-lactamases and compounds bearing a methoxy side chain on the alpha-face of the beta-lactam ring: kinetic and molecular modelling studies. Biochem J. 1993 Aug;293(Pt 3):607-11. DOI: 10.1042/bj2930607</RefTotal> <RefLink>https://doi.org/10.1042/bj2930607</RefLink> </Reference> <Reference refNo="10"> <RefAuthor>Rodriguez-Villalobos H</RefAuthor> <RefAuthor>Malaviolle V</RefAuthor> <RefAuthor>Frankard J</RefAuthor> <RefAuthor>de Mendonça R</RefAuthor> <RefAuthor>Nonhoff C</RefAuthor> <RefAuthor>Struelens MJ</RefAuthor> <RefTitle>In vitro activity of temocillin against extended spectrum beta-lactamase-producing Escherichia coli</RefTitle> <RefYear>2006</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>771-4</RefPage> <RefTotal>Rodriguez-Villalobos H, Malaviolle V, Frankard J, de Mendonça R, Nonhoff C, Struelens MJ. In vitro activity of temocillin against extended spectrum beta-lactamase-producing Escherichia coli. J Antimicrob Chemother. 2006 Apr;57(4):771-4. DOI: 10.1093/jac/dkl046</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkl046</RefLink> </Reference> <Reference refNo="11"> <RefAuthor>Rodriguez-Villalobos H</RefAuthor> <RefAuthor>Bogaerts P</RefAuthor> <RefAuthor>Berhin C</RefAuthor> <RefAuthor>Bauraing C</RefAuthor> <RefAuthor>Deplano A</RefAuthor> <RefAuthor>Montesinos I</RefAuthor> <RefAuthor>de Mendonça R</RefAuthor> <RefAuthor>Jans B</RefAuthor> <RefAuthor>Glupczynski Y</RefAuthor> <RefTitle>Trends in production of extended-spectrum beta-lactamases among Enterobacteriaceae of clinical interest: results of a nationwide survey in Belgian hospitals</RefTitle> <RefYear>2011</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>37-47</RefPage> <RefTotal>Rodriguez-Villalobos H, Bogaerts P, Berhin C, Bauraing C, Deplano A, Montesinos I, de Mendonça R, Jans B, Glupczynski Y. Trends in production of extended-spectrum beta-lactamases among Enterobacteriaceae of clinical interest: results of a nationwide survey in Belgian hospitals. J Antimicrob Chemother. 2011 Jan;66(1):37-47. DOI: 10.1093/jac/dkq388</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkq388</RefLink> </Reference> <Reference refNo="12"> <RefAuthor>Livermore DM</RefAuthor> <RefAuthor>Hope R</RefAuthor> <RefAuthor>Fagan EJ</RefAuthor> <RefAuthor>Warner M</RefAuthor> <RefAuthor>Woodford N</RefAuthor> <RefAuthor>Potz N</RefAuthor> <RefTitle>Activity of temocillin against prevalent ESBL- and AmpC-producing Enterobacteriaceae from south-east England</RefTitle> <RefYear>2006</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>1012-4</RefPage> <RefTotal>Livermore DM, Hope R, Fagan EJ, Warner M, Woodford N, Potz N. Activity of temocillin against prevalent ESBL- and AmpC-producing Enterobacteriaceae from south-east England. J Antimicrob Chemother. 2006 May;57(5):1012-4. DOI: 10.1093/jac/dkl043</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkl043</RefLink> </Reference> <Reference refNo="13"> <RefAuthor>Laterre PF</RefAuthor> <RefAuthor>Wittebole X</RefAuthor> <RefAuthor>Van de Velde S</RefAuthor> <RefAuthor>Muller AE</RefAuthor> <RefAuthor>Mouton JW</RefAuthor> <RefAuthor>Carryn S</RefAuthor> <RefAuthor>Tulkens PM</RefAuthor> <RefAuthor>Dugernier T</RefAuthor> <RefTitle>Temocillin (6 g daily) in critically ill patients: continuous infusion versus three times daily administration</RefTitle> <RefYear>2015</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>891-8</RefPage> <RefTotal>Laterre PF, Wittebole X, Van de Velde S, Muller AE, Mouton JW, Carryn S, Tulkens PM, Dugernier T. Temocillin (6 g daily) in critically ill patients: continuous infusion versus three times daily administration. J Antimicrob Chemother. 2015 Mar;70(3):891-8. DOI: 10.1093/jac/dku465</RefTotal> <RefLink>https://doi.org/10.1093/jac/dku465</RefLink> </Reference> <Reference refNo="14"> <RefAuthor>Balakrishnan I</RefAuthor> <RefAuthor>Awad-El-Kariem FM</RefAuthor> <RefAuthor>Aali A</RefAuthor> <RefAuthor>Kumari P</RefAuthor> <RefAuthor>Mulla R</RefAuthor> <RefAuthor>Tan B</RefAuthor> <RefAuthor>Brudney D</RefAuthor> <RefAuthor>Ladenheim D</RefAuthor> <RefAuthor>Ghazy A</RefAuthor> <RefAuthor>Khan I</RefAuthor> <RefAuthor>Virgincar N</RefAuthor> <RefAuthor>Iyer S</RefAuthor> <RefAuthor>Carryn S</RefAuthor> <RefAuthor>Van de Velde S</RefAuthor> <RefTitle>Temocillin use in England: clinical and microbiological efficacies in infections caused by extended-spectrum and/or derepressed AmpC β-lactamase-producing Enterobacteriaceae</RefTitle> <RefYear>2011</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>2628-31</RefPage> <RefTotal>Balakrishnan I, Awad-El-Kariem FM, Aali A, Kumari P, Mulla R, Tan B, Brudney D, Ladenheim D, Ghazy A, Khan I, Virgincar N, Iyer S, Carryn S, Van de Velde S. Temocillin use in England: clinical and microbiological efficacies in infections caused by extended-spectrum and/or derepressed AmpC β-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2011 Nov;66(11):2628-31. DOI: 10.1093/jac/dkr317</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkr317</RefLink> </Reference> <Reference refNo="15"> <RefAuthor>Shlaes DM</RefAuthor> <RefTitle>New β-lactam-β-lactamase inhibitor combinations in clinical development</RefTitle> <RefYear>2013</RefYear> <RefJournal>Ann N Y Acad Sci</RefJournal> <RefPage>105-14</RefPage> <RefTotal>Shlaes DM. New β-lactam-β-lactamase inhibitor combinations in clinical development. Ann N Y Acad Sci. 2013 Jan;1277:105-14. DOI: 10.1111/nyas.12010</RefTotal> <RefLink>https://doi.org/10.1111/nyas.12010</RefLink> </Reference> <Reference refNo="16"> <RefAuthor>Drawz SM</RefAuthor> <RefAuthor>Papp-Wallace KM</RefAuthor> <RefAuthor>Bonomo RA</RefAuthor> <RefTitle>New β-lactamase inhibitors: a therapeutic renaissance in an MDR world</RefTitle> <RefYear>2014</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>1835-46</RefPage> <RefTotal>Drawz SM, Papp-Wallace KM, Bonomo RA. New β-lactamase inhibitors: a therapeutic renaissance in an MDR world. Antimicrob Agents Chemother. 2014;58(4):1835-46. DOI: 10.1128/AAC.00826-13</RefTotal> <RefLink>https://doi.org/10.1128/AAC.00826-13</RefLink> </Reference> <Reference refNo="17"> <RefAuthor>Zhanel GG</RefAuthor> <RefAuthor>Lawson CD</RefAuthor> <RefAuthor>Adam H</RefAuthor> <RefAuthor>Schweizer F</RefAuthor> <RefAuthor>Zelenitsky S</RefAuthor> <RefAuthor>Lagacé-Wiens PR</RefAuthor> <RefAuthor>Denisuik A</RefAuthor> <RefAuthor>Rubinstein E</RefAuthor> <RefAuthor>Gin AS</RefAuthor> <RefAuthor>Hoban DJ</RefAuthor> <RefAuthor>Lynch JP 3rd</RefAuthor> <RefAuthor>Karlowsky JA</RefAuthor> <RefTitle>Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination</RefTitle> <RefYear>2013</RefYear> <RefJournal>Drugs</RefJournal> <RefPage>159-77</RefPage> <RefTotal>Zhanel GG, Lawson CD, Adam H, Schweizer F, Zelenitsky S, Lagacé-Wiens PR, Denisuik A, Rubinstein E, Gin AS, Hoban DJ, Lynch JP 3rd, Karlowsky JA. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs. 2013 Feb;73(2):159-77. DOI: 10.1007/s40265-013-0013-7</RefTotal> <RefLink>https://doi.org/10.1007/s40265-013-0013-7</RefLink> </Reference> <Reference refNo="18"> <RefAuthor>Nicolau DP</RefAuthor> <RefAuthor>Siew L</RefAuthor> <RefAuthor>Armstrong J</RefAuthor> <RefAuthor>Li J</RefAuthor> <RefAuthor>Edeki T</RefAuthor> <RefAuthor>Learoyd M</RefAuthor> <RefAuthor>Das S</RefAuthor> <RefTitle>Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens</RefTitle> <RefYear>2015</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>2862-9</RefPage> <RefTotal>Nicolau DP, Siew L, Armstrong J, Li J, Edeki T, Learoyd M, Das S. Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens. J Antimicrob Chemother. 2015 Oct;70(10):2862-9. DOI: 10.1093/jac/dkv170</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkv170</RefLink> </Reference> <Reference refNo="19"> <RefAuthor>Zhanel GG</RefAuthor> <RefAuthor>Chung P</RefAuthor> <RefAuthor>Adam H</RefAuthor> <RefAuthor>Zelenitsky S</RefAuthor> <RefAuthor>Denisuik A</RefAuthor> <RefAuthor>Schweizer F</RefAuthor> <RefAuthor>Lagacé-Wiens PR</RefAuthor> <RefAuthor>Rubinstein E</RefAuthor> <RefAuthor>Gin AS</RefAuthor> <RefAuthor>Walkty A</RefAuthor> <RefAuthor>Hoban DJ</RefAuthor> <RefAuthor>Lynch JP 3rd</RefAuthor> <RefAuthor>Karlowsky JA</RefAuthor> <RefTitle>Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli</RefTitle> <RefYear>2014</RefYear> <RefJournal>Drugs</RefJournal> <RefPage>31-51</RefPage> <RefTotal>Zhanel GG, Chung P, Adam H, Zelenitsky S, Denisuik A, Schweizer F, Lagacé-Wiens PR, Rubinstein E, Gin AS, Walkty A, Hoban DJ, Lynch JP 3rd, Karlowsky JA. Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 2014 Jan;74(1):31-51. DOI: 10.1007/s40265-013-0168-2</RefTotal> <RefLink>https://doi.org/10.1007/s40265-013-0168-2</RefLink> </Reference> <Reference refNo="20"> <RefAuthor>Moyá B</RefAuthor> <RefAuthor>Zamorano L</RefAuthor> <RefAuthor>Juan C</RefAuthor> <RefAuthor>Ge Y</RefAuthor> <RefAuthor>Oliver A</RefAuthor> <RefTitle>Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa</RefTitle> <RefYear>2010</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>3933-7</RefPage> <RefTotal>Moyá B, Zamorano L, Juan C, Ge Y, Oliver A. Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2010 Sep;54(9):3933-7. DOI: 10.1128/AAC.00296-10</RefTotal> <RefLink>https://doi.org/10.1128/AAC.00296-10</RefLink> </Reference> <Reference refNo="21"> <RefAuthor>Chandorkar G</RefAuthor> <RefAuthor>Xiao A</RefAuthor> <RefAuthor>Mouksassi MS</RefAuthor> <RefAuthor>Hershberger E</RefAuthor> <RefAuthor>Krishna G</RefAuthor> <RefTitle>Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections</RefTitle> <RefYear>2015</RefYear> <RefJournal>J Clin Pharmacol</RefJournal> <RefPage>230-9</RefPage> <RefTotal>Chandorkar G, Xiao A, Mouksassi MS, Hershberger E, Krishna G. Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections. J Clin Pharmacol. 2015 Feb;55(2):230-9. DOI: 10.1002/jcph.395</RefTotal> <RefLink>https://doi.org/10.1002/jcph.395</RefLink> </Reference> <Reference refNo="22"> <RefAuthor>Bassetti M</RefAuthor> <RefAuthor>Righi E</RefAuthor> <RefTitle>Ceftolozane/tazobactam for the treatment of complicated urinary tract and intra-abdominal infections</RefTitle> <RefYear>2015</RefYear> <RefJournal>Future Microbiol</RefJournal> <RefPage>151-60</RefPage> <RefTotal>Bassetti M, Righi E. Ceftolozane/tazobactam for the treatment of complicated urinary tract and intra-abdominal infections. Future Microbiol. 2015;10(2):151-60. DOI: 10.2217/fmb.14.112</RefTotal> <RefLink>https://doi.org/10.2217/fmb.14.112</RefLink> </Reference> <Reference refNo="23"> <RefAuthor>Solomkin J</RefAuthor> <RefAuthor>Hershberger E</RefAuthor> <RefAuthor>Miller B</RefAuthor> <RefAuthor>Popejoy M</RefAuthor> <RefAuthor>Friedland I</RefAuthor> <RefAuthor>Steenbergen J</RefAuthor> <RefAuthor>Yoon M</RefAuthor> <RefAuthor>Collins S</RefAuthor> <RefAuthor>Yuan G</RefAuthor> <RefAuthor>Barie PS</RefAuthor> <RefAuthor>Eckmann C</RefAuthor> <RefTitle>Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI)</RefTitle> <RefYear>2015</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>1462-71</RefPage> <RefTotal>Solomkin J, Hershberger E, Miller B, Popejoy M, Friedland I, Steenbergen J, Yoon M, Collins S, Yuan G, Barie PS, Eckmann C. Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI). Clin Infect Dis. 2015 May;60(10):1462-71. DOI: 10.1093/cid/civ097</RefTotal> <RefLink>https://doi.org/10.1093/cid/civ097</RefLink> </Reference> <Reference refNo="24"> <RefAuthor>Wagenlehner FM</RefAuthor> <RefAuthor>Umeh O</RefAuthor> <RefAuthor>Steenbergen J</RefAuthor> <RefAuthor>Yuan G</RefAuthor> <RefAuthor>Darouiche RO</RefAuthor> <RefTitle>Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI)</RefTitle> <RefYear>2015</RefYear> <RefJournal>Lancet</RefJournal> <RefPage>1949-56</RefPage> <RefTotal>Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet. 2015 May 16;385(9981):1949-56. DOI: 10.1016/S0140-6736(14)62220-0</RefTotal> <RefLink>https://doi.org/10.1016/S0140-6736(14)62220-0</RefLink> </Reference> <Reference refNo="25"> <RefAuthor>Bazaz R</RefAuthor> <RefAuthor>Chapman AL</RefAuthor> <RefAuthor>Winstanley TG</RefAuthor> <RefTitle>Ertapenem administered as outpatient parenteral antibiotic therapy for urinary tract infections caused by extended-spectrum-beta-lactamase-producing Gram-negative organisms</RefTitle> <RefYear>2010</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>1510-3</RefPage> <RefTotal>Bazaz R, Chapman AL, Winstanley TG. Ertapenem administered as outpatient parenteral antibiotic therapy for urinary tract infections caused by extended-spectrum-beta-lactamase-producing Gram-negative organisms. J Antimicrob Chemother. 2010 Jul;65(7):1510-3. DOI: 10.1093/jac/dkq152</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkq152</RefLink> </Reference> <Reference refNo="26"> <RefAuthor>Thalhammer F</RefAuthor> <RefAuthor>Grisold A</RefAuthor> <RefAuthor>Hörmann C</RefAuthor> <RefAuthor>Krafft P</RefAuthor> <RefAuthor>Krause R</RefAuthor> <RefAuthor>Lass-Flörl C</RefAuthor> <RefAuthor>Lechner A</RefAuthor> <RefAuthor>Schima W</RefAuthor> <RefAuthor>Teleky B</RefAuthor> <RefAuthor>Weiss G</RefAuthor> <RefAuthor>Wenisch C</RefAuthor> <RefAuthor>Wenzl E</RefAuthor> <RefAuthor>Wimmer P</RefAuthor> <RefAuthor>Zeitlinger M</RefAuthor> <RefTitle>Consensus Statement Intraabdominelle Infektionen</RefTitle> <RefYear>2011</RefYear> <RefJournal>Osterr Arzteztg</RefJournal> <RefPage>1–8</RefPage> <RefTotal>Thalhammer F, Grisold A, Hörmann C, Krafft P, Krause R, Lass-Flörl C, Lechner A, Schima W, Teleky B, Weiss G, Wenisch C, Wenzl E, Wimmer P, Zeitlinger M. Consensus Statement Intraabdominelle Infektionen. Osterr Arzteztg. 2011;Supplementum März:1–8.</RefTotal> </Reference> <Reference refNo="27"> <RefAuthor>Muralidharan G</RefAuthor> <RefAuthor>Micalizzi M</RefAuthor> <RefAuthor>Speth J</RefAuthor> <RefAuthor>Raible D</RefAuthor> <RefAuthor>Troy S</RefAuthor> <RefTitle>Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects</RefTitle> <RefYear>2005</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>220-9</RefPage> <RefTotal>Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother. 2005 Jan;49(1):220-9. DOI: 10.1128/AAC.49.1.220-229.2005</RefTotal> <RefLink>https://doi.org/10.1128/AAC.49.1.220-229.2005</RefLink> </Reference> <Reference refNo="28"> <RefAuthor>Kim NH</RefAuthor> <RefAuthor>Hwang JH</RefAuthor> <RefAuthor>Song KH</RefAuthor> <RefAuthor>Choe PG</RefAuthor> <RefAuthor>Kim ES</RefAuthor> <RefAuthor>Park SW</RefAuthor> <RefAuthor>Kim HB</RefAuthor> <RefAuthor>Kim NJ</RefAuthor> <RefAuthor>Park WB</RefAuthor> <RefAuthor>Oh MD</RefAuthor> <RefTitle>Tigecycline in carbapenem-resistant Acinetobacter baumannii bacteraemia: susceptibility and clinical outcome</RefTitle> <RefYear>2013</RefYear> <RefJournal>Scand J Infect Dis</RefJournal> <RefPage>315-9</RefPage> <RefTotal>Kim NH, Hwang JH, Song KH, Choe PG, Kim ES, Park SW, Kim HB, Kim NJ, Park WB, Oh MD. Tigecycline in carbapenem-resistant Acinetobacter baumannii bacteraemia: susceptibility and clinical outcome. Scand J Infect Dis. 2013 Apr;45(4):315-9. DOI: 10.3109/00365548.2012.732705</RefTotal> <RefLink>https://doi.org/10.3109/00365548.2012.732705</RefLink> </Reference> <Reference refNo="29"> <RefAuthor>Freire AT</RefAuthor> <RefAuthor>Melnyk V</RefAuthor> <RefAuthor>Kim MJ</RefAuthor> <RefAuthor>Datsenko O</RefAuthor> <RefAuthor>Dzyublik O</RefAuthor> <RefAuthor>Glumcher F</RefAuthor> <RefAuthor>Chuang YC</RefAuthor> <RefAuthor>Maroko RT</RefAuthor> <RefAuthor>Dukart G</RefAuthor> <RefAuthor>Cooper CA</RefAuthor> <RefAuthor>Korth-Bradley JM</RefAuthor> <RefAuthor>Dartois N</RefAuthor> <RefAuthor>Gandjini H</RefAuthor> <RefAuthor> 311 Study Group</RefAuthor> <RefTitle>Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia</RefTitle> <RefYear>2010</RefYear> <RefJournal>Diagn Microbiol Infect Dis</RefJournal> <RefPage>140-51</RefPage> <RefTotal>Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, Chuang YC, Maroko RT, Dukart G, Cooper CA, Korth-Bradley JM, Dartois N, Gandjini H; 311 Study Group. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis. 2010 Oct;68(2):140-51. DOI: 10.1016/j.diagmicrobio.2010.05.012</RefTotal> <RefLink>https://doi.org/10.1016/j.diagmicrobio.2010.05.012</RefLink> </Reference> <Reference refNo="30"> <RefAuthor>Pichardo C</RefAuthor> <RefAuthor>Pachón-Ibañez ME</RefAuthor> <RefAuthor>Docobo-Perez F</RefAuthor> <RefAuthor>López-Rojas R</RefAuthor> <RefAuthor>Jiménez-Mejías ME</RefAuthor> <RefAuthor>Garcia-Curiel A</RefAuthor> <RefAuthor>Pachon J</RefAuthor> <RefTitle>Efficacy of tigecycline vs. imipenem in the treatment of experimental Acinetobacter baumannii murine pneumonia</RefTitle> <RefYear>2010</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>527-31</RefPage> <RefTotal>Pichardo C, Pachón-Ibañez ME, Docobo-Perez F, López-Rojas R, Jiménez-Mejías ME, Garcia-Curiel A, Pachon J. Efficacy of tigecycline vs. imipenem in the treatment of experimental Acinetobacter baumannii murine pneumonia. Eur J Clin Microbiol Infect Dis. 2010 May;29(5):527-31. DOI: 10.1007/s10096-010-0890-6</RefTotal> <RefLink>https://doi.org/10.1007/s10096-010-0890-6</RefLink> </Reference> <Reference refNo="31"> <RefAuthor>Ramirez J</RefAuthor> <RefAuthor>Dartois N</RefAuthor> <RefAuthor>Gandjini H</RefAuthor> <RefAuthor>Yan JL</RefAuthor> <RefAuthor>Korth-Bradley J</RefAuthor> <RefAuthor>McGovern PC</RefAuthor> <RefTitle>Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia</RefTitle> <RefYear>2013</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>1756-62</RefPage> <RefTotal>Ramirez J, Dartois N, Gandjini H, Yan JL, Korth-Bradley J, McGovern PC. Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia. Antimicrob Agents Chemother. 2013 Apr;57(4):1756-62. DOI: 10.1128/AAC.01232-12</RefTotal> <RefLink>https://doi.org/10.1128/AAC.01232-12</RefLink> </Reference> <Reference refNo="32"> <RefAuthor>Docobo-Pérez F</RefAuthor> <RefAuthor>Drusano GL</RefAuthor> <RefAuthor>Johnson A</RefAuthor> <RefAuthor>Goodwin J</RefAuthor> <RefAuthor>Whalley S</RefAuthor> <RefAuthor>Ramos-Martín V</RefAuthor> <RefAuthor>Ballestero-Tellez M</RefAuthor> <RefAuthor>Rodriguez-Martinez JM</RefAuthor> <RefAuthor>Conejo MC</RefAuthor> <RefAuthor>van Guilder M</RefAuthor> <RefAuthor>Rodríguez-Baño J</RefAuthor> <RefAuthor>Pascual A</RefAuthor> <RefAuthor>Hope WW</RefAuthor> <RefTitle>Pharmacodynamics of fosfomycin: insights into clinical use for antimicrobial resistance</RefTitle> <RefYear>2015</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>5602-10</RefPage> <RefTotal>Docobo-Pérez F, Drusano GL, Johnson A, Goodwin J, Whalley S, Ramos-Martín V, Ballestero-Tellez M, Rodriguez-Martinez JM, Conejo MC, van Guilder M, Rodríguez-Baño J, Pascual A, Hope WW. Pharmacodynamics of fosfomycin: insights into clinical use for antimicrobial resistance. Antimicrob Agents Chemother. 2015 Sep;59(9):5602-10. DOI: 10.1128/AAC.00752-15</RefTotal> <RefLink>https://doi.org/10.1128/AAC.00752-15</RefLink> </Reference> <Reference refNo="33"> <RefAuthor>Walsh CC</RefAuthor> <RefAuthor>McIntosh MP</RefAuthor> <RefAuthor>Peleg AY</RefAuthor> <RefAuthor>Kirkpatrick CM</RefAuthor> <RefAuthor>Bergen PJ</RefAuthor> <RefTitle>In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa</RefTitle> <RefYear>2015</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>3042-50</RefPage> <RefTotal>Walsh CC, McIntosh MP, Peleg AY, Kirkpatrick CM, Bergen PJ. In vitro pharmacodynamics of fosfomycin against clinical isolates of Pseudomonas aeruginosa. J Antimicrob Chemother. 2015 Nov;70(11):3042-50. DOI: 10.1093/jac/dkv221</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkv221</RefLink> </Reference> <Reference refNo="34"> <RefAuthor>Kühnen E</RefAuthor> <RefAuthor>Pfeifer G</RefAuthor> <RefAuthor>Frenkel C</RefAuthor> <RefTitle>Penetration of fosfomycin into cerebrospinal fluid across non-inflamed and inflamed meninges</RefTitle> <RefYear>1987</RefYear> <RefJournal>Infection</RefJournal> <RefPage>422-4</RefPage> <RefTotal>Kühnen E, Pfeifer G, Frenkel C. Penetration of fosfomycin into cerebrospinal fluid across non-inflamed and inflamed meninges. Infection. 1987 Nov-Dec;15(6):422-4. DOI: 10.1007/BF01647220</RefTotal> <RefLink>https://doi.org/10.1007/BF01647220</RefLink> </Reference> <Reference refNo="35"> <RefAuthor>Trapnell BC</RefAuthor> <RefAuthor>McColley SA</RefAuthor> <RefAuthor>Kissner DG</RefAuthor> <RefAuthor>Rolfe MW</RefAuthor> <RefAuthor>Rosen JM</RefAuthor> <RefAuthor>McKevitt M</RefAuthor> <RefAuthor>Moorehead L</RefAuthor> <RefAuthor>Montgomery AB</RefAuthor> <RefAuthor>Geller DE</RefAuthor> <RefAuthor> Phase 2 FTI Study Group</RefAuthor> <RefTitle>Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with pseudomonas airway infection</RefTitle> <RefYear>2012</RefYear> <RefJournal>Am J Respir Crit Care Med</RefJournal> <RefPage>171-8</RefPage> <RefTotal>Trapnell BC, McColley SA, Kissner DG, Rolfe MW, Rosen JM, McKevitt M, Moorehead L, Montgomery AB, Geller DE; Phase 2 FTI Study Group. Fosfomycin/tobramycin for inhalation in patients with cystic fibrosis with pseudomonas airway infection. Am J Respir Crit Care Med. 2012 Jan;185(2):171-8. DOI: 10.1164/rccm.201105-0924OC</RefTotal> <RefLink>https://doi.org/10.1164/rccm.201105-0924OC</RefLink> </Reference> <Reference refNo="36"> <RefAuthor>Falagas ME</RefAuthor> <RefAuthor>Kastoris AC</RefAuthor> <RefAuthor>Kapaskelis AM</RefAuthor> <RefAuthor>Karageorgopoulos DE</RefAuthor> <RefTitle>Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review</RefTitle> <RefYear>2010</RefYear> <RefJournal>Lancet Infect Dis</RefJournal> <RefPage>43-50</RefPage> <RefTotal>Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgopoulos DE. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis. 2010 Jan;10(1):43-50. DOI: 10.1016/S1473-3099(09)70325-1</RefTotal> <RefLink>https://doi.org/10.1016/S1473-3099(09)70325-1</RefLink> </Reference> <Reference refNo="37"> <RefAuthor>Oteo J</RefAuthor> <RefAuthor>Bautista V</RefAuthor> <RefAuthor>Lara N</RefAuthor> <RefAuthor>Cuevas O</RefAuthor> <RefAuthor>Arroyo M</RefAuthor> <RefAuthor>Fernández S</RefAuthor> <RefAuthor>Lázaro E</RefAuthor> <RefAuthor>de Abajo FJ</RefAuthor> <RefAuthor>Campos J</RefAuthor> <RefAuthor> Spanish ESBL-EARS-Net Study Group</RefAuthor> <RefTitle>Parallel increase in community use of fosfomycin and resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli</RefTitle> <RefYear>2010</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>2459-63</RefPage> <RefTotal>Oteo J, Bautista V, Lara N, Cuevas O, Arroyo M, Fernández S, Lázaro E, de Abajo FJ, Campos J; Spanish ESBL-EARS-Net Study Group. Parallel increase in community use of fosfomycin and resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. J Antimicrob Chemother. 2010 Nov;65(11):2459-63. DOI: 10.1093/jac/dkq346</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkq346</RefLink> </Reference> <Reference refNo="38"> <RefAuthor>Falagas ME</RefAuthor> <RefAuthor>Kasiakou SK</RefAuthor> <RefTitle>Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections</RefTitle> <RefYear>2005</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>1333-41</RefPage> <RefTotal>Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis. 2005 May;40(9):1333-41. DOI: 10.1086/429323</RefTotal> <RefLink>https://doi.org/10.1086/429323</RefLink> </Reference> <Reference refNo="39"> <RefAuthor>Mohamed AF</RefAuthor> <RefAuthor>Karaiskos I</RefAuthor> <RefAuthor>Plachouras D</RefAuthor> <RefAuthor>Karvanen M</RefAuthor> <RefAuthor>Pontikis K</RefAuthor> <RefAuthor>Jansson B</RefAuthor> <RefAuthor>Papadomichelakis E</RefAuthor> <RefAuthor>Antoniadou A</RefAuthor> <RefAuthor>Giamarellou H</RefAuthor> <RefAuthor>Armaganidis A</RefAuthor> <RefAuthor>Cars O</RefAuthor> <RefAuthor>Friberg LE</RefAuthor> <RefTitle>Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill</RefTitle> <RefYear>2012</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>4241-9</RefPage> <RefTotal>Mohamed AF, Karaiskos I, Plachouras D, Karvanen M, Pontikis K, Jansson B, Papadomichelakis E, Antoniadou A, Giamarellou H, Armaganidis A, Cars O, Friberg LE. Application of a loading dose of colistin methanesulfonate in critically ill patients: population pharmacokinetics, protein binding, and prediction of bacterial kill. Antimicrob Agents Chemother. 2012 Aug;56(8):4241-9. DOI: 10.1128/AAC.06426-11</RefTotal> <RefLink>https://doi.org/10.1128/AAC.06426-11</RefLink> </Reference> <Reference refNo="40"> <RefAuthor>Landersdorfer CB</RefAuthor> <RefAuthor>Nation RL</RefAuthor> <RefTitle>Colistin: how should it be dosed for the critically ill?</RefTitle> <RefYear>2015</RefYear> <RefJournal>Semin Respir Crit Care Med</RefJournal> <RefPage>126-35</RefPage> <RefTotal>Landersdorfer CB, Nation RL. Colistin: how should it be dosed for the critically ill?. Semin Respir Crit Care Med. 2015 Feb;36(1):126-35. DOI: 10.1055/s-0034-1398390</RefTotal> <RefLink>https://doi.org/10.1055/s-0034-1398390</RefLink> </Reference> <Reference refNo="41"> <RefAuthor>Yapa SWS</RefAuthor> <RefAuthor>Li J</RefAuthor> <RefAuthor>Patel K</RefAuthor> <RefAuthor>Wilson JW</RefAuthor> <RefAuthor>Dooley MJ</RefAuthor> <RefAuthor>George J</RefAuthor> <RefAuthor>Clark D</RefAuthor> <RefAuthor>Poole S</RefAuthor> <RefAuthor>Williams E</RefAuthor> <RefAuthor>Porter CJ</RefAuthor> <RefAuthor>Nation RL</RefAuthor> <RefAuthor>McIntosh MP</RefAuthor> <RefTitle>Pulmonary and systemic pharmacokinetics of inhaled and intravenous colistin methanesulfonate in cystic fibrosis patients: targeting advantage of inhalational administration</RefTitle> <RefYear>2014</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2570-9</RefPage> <RefTotal>Yapa SWS, Li J, Patel K, Wilson JW, Dooley MJ, George J, Clark D, Poole S, Williams E, Porter CJ, Nation RL, McIntosh MP. Pulmonary and systemic pharmacokinetics of inhaled and intravenous colistin methanesulfonate in cystic fibrosis patients: targeting advantage of inhalational administration. Antimicrob Agents Chemother. 2014 05;58(5):2570-9. DOI: 10.1128/AAC.01705-13</RefTotal> <RefLink>https://doi.org/10.1128/AAC.01705-13</RefLink> </Reference> <Reference refNo="42"> <RefAuthor>Lu Q</RefAuthor> <RefAuthor>Girardi C</RefAuthor> <RefAuthor>Zhang M</RefAuthor> <RefAuthor>Bouhemad B</RefAuthor> <RefAuthor>Louchahi K</RefAuthor> <RefAuthor>Petitjean O</RefAuthor> <RefAuthor>Wallet F</RefAuthor> <RefAuthor>Becquemin MH</RefAuthor> <RefAuthor>Le Naour G</RefAuthor> <RefAuthor>Marquette CH</RefAuthor> <RefAuthor>Rouby JJ</RefAuthor> <RefTitle>Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa</RefTitle> <RefYear>2010</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>1147-55</RefPage> <RefTotal>Lu Q, Girardi C, Zhang M, Bouhemad B, Louchahi K, Petitjean O, Wallet F, Becquemin MH, Le Naour G, Marquette CH, Rouby JJ. Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa. Intensive Care Med. 2010 Jul;36(7):1147-55. DOI: 10.1007/s00134-010-1879-4</RefTotal> <RefLink>https://doi.org/10.1007/s00134-010-1879-4</RefLink> </Reference> <Reference refNo="43"> <RefAuthor>Athanassa ZE</RefAuthor> <RefAuthor>Markantonis SL</RefAuthor> <RefAuthor>Fousteri MZ</RefAuthor> <RefAuthor>Myrianthefs PM</RefAuthor> <RefAuthor>Boutzouka EG</RefAuthor> <RefAuthor>Tsakris A</RefAuthor> <RefAuthor>Baltopoulos GJ</RefAuthor> <RefTitle>Pharmacokinetics of inhaled colistimethate sodium (CMS) in mechanically ventilated critically ill patients</RefTitle> <RefYear>2012</RefYear> <RefJournal>Intensive Care Med</RefJournal> <RefPage>1779-86</RefPage> <RefTotal>Athanassa ZE, Markantonis SL, Fousteri MZ, Myrianthefs PM, Boutzouka EG, Tsakris A, Baltopoulos GJ. Pharmacokinetics of inhaled colistimethate sodium (CMS) in mechanically ventilated critically ill patients. Intensive Care Med. 2012 Nov;38(11):1779-86. DOI: 10.1007/s00134-012-2628-7</RefTotal> <RefLink>https://doi.org/10.1007/s00134-012-2628-7</RefLink> </Reference> <Reference refNo="44"> <RefAuthor>Tumbarello M</RefAuthor> <RefAuthor>De Pascale G</RefAuthor> <RefAuthor>Trecarichi EM</RefAuthor> <RefAuthor>De Martino S</RefAuthor> <RefAuthor>Bello G</RefAuthor> <RefAuthor>Maviglia R</RefAuthor> <RefAuthor>Spanu T</RefAuthor> <RefAuthor>Antonelli M</RefAuthor> <RefTitle>Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria</RefTitle> <RefYear>2013</RefYear> <RefJournal>Chest</RefJournal> <RefPage>1768-1775</RefPage> <RefTotal>Tumbarello M, De Pascale G, Trecarichi EM, De Martino S, Bello G, Maviglia R, Spanu T, Antonelli M. Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria. Chest. 2013 Dec;144(6):1768-1775. DOI: 10.1378/chest.13-1018</RefTotal> <RefLink>https://doi.org/10.1378/chest.13-1018</RefLink> </Reference> <Reference refNo="45"> <RefAuthor>Kuo SC</RefAuthor> <RefAuthor>Lee YT</RefAuthor> <RefAuthor>Yang SP</RefAuthor> <RefAuthor>Chen CP</RefAuthor> <RefAuthor>Chen TL</RefAuthor> <RefAuthor>Hsieh SL</RefAuthor> <RefAuthor>Siu LK</RefAuthor> <RefAuthor>Fung CP</RefAuthor> <RefTitle>Eradication of multidrug-resistant Acinetobacter baumannii from the respiratory tract with inhaled colistin methanesulfonate: a matched case-control study</RefTitle> <RefYear>2012</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>870-6</RefPage> <RefTotal>Kuo SC, Lee YT, Yang SP, Chen CP, Chen TL, Hsieh SL, Siu LK, Fung CP. Eradication of multidrug-resistant Acinetobacter baumannii from the respiratory tract with inhaled colistin methanesulfonate: a matched case-control study. Clin Microbiol Infect. 2012 Sep;18(9):870-6. DOI: 10.1111/j.1469-0691.2011.03682.x</RefTotal> <RefLink>https://doi.org/10.1111/j.1469-0691.2011.03682.x</RefLink> </Reference> <Reference refNo="46"> <RefAuthor>Kollef MH</RefAuthor> <RefAuthor>Hamilton CW</RefAuthor> <RefAuthor>Montgomery AB</RefAuthor> <RefTitle>Aerosolized antibiotics: do they add to the treatment of pneumonia?</RefTitle> <RefYear>2013</RefYear> <RefJournal>Curr Opin Infect Dis</RefJournal> <RefPage>538-44</RefPage> <RefTotal>Kollef MH, Hamilton CW, Montgomery AB. Aerosolized antibiotics: do they add to the treatment of pneumonia?. Curr Opin Infect Dis. 2013 Dec;26(6):538-44. DOI: 10.1097/QCO.0000000000000004</RefTotal> <RefLink>https://doi.org/10.1097/QCO.0000000000000004</RefLink> </Reference> <Reference refNo="47"> <RefAuthor>de Kraker ME</RefAuthor> <RefAuthor>Davey PG</RefAuthor> <RefAuthor>Grundmann H</RefAuthor> <RefAuthor> BURDEN study group</RefAuthor> <RefTitle>Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: estimating the burden of antibiotic resistance in Europe</RefTitle> <RefYear>2011</RefYear> <RefJournal>PLoS Med</RefJournal> <RefPage>e1001104</RefPage> <RefTotal>de Kraker ME, Davey PG, Grundmann H; BURDEN study group. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: estimating the burden of antibiotic resistance in Europe. PLoS Med. 2011 Oct;8(10):e1001104. DOI: 10.1371/journal.pmed.1001104</RefTotal> <RefLink>https://doi.org/10.1371/journal.pmed.1001104</RefLink> </Reference> <Reference refNo="48"> <RefAuthor>Forstner C</RefAuthor> <RefAuthor>Hagel S</RefAuthor> <RefAuthor>Löffler B</RefAuthor> <RefAuthor>Thalhammer F</RefAuthor> <RefAuthor>Pletz MW</RefAuthor> <RefTitle>Therapieoptionen bei Infektion durch nosokomiale multiresistente Erreger</RefTitle> <RefYear>2014</RefYear> <RefJournal>Krankenhaushyg up2date</RefJournal> <RefPage>301–16</RefPage> <RefTotal>Forstner C, Hagel S, Löffler B, Thalhammer F, Pletz MW. Therapieoptionen bei Infektion durch nosokomiale multiresistente Erreger. Krankenhaushyg up2date. 2014;9(4):301–16. DOI: 10.1055/s-0034-1391290</RefTotal> <RefLink>https://doi.org/10.1055/s-0034-1391290</RefLink> </Reference> <Reference refNo="49"> <RefAuthor>Winkler ML</RefAuthor> <RefAuthor>Papp-Wallace KM</RefAuthor> <RefAuthor>Bonomo RA</RefAuthor> <RefTitle>Activity of ceftazidime/avibactam against isogenic strains of Escherichia coli containing KPC and SHV β-lactamases with single amino acid substitutions in the Ω-loop</RefTitle> <RefYear>2015</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>2279-86</RefPage> <RefTotal>Winkler ML, Papp-Wallace KM, Bonomo RA. Activity of ceftazidime/avibactam against isogenic strains of Escherichia coli containing KPC and SHV β-lactamases with single amino acid substitutions in the Ω-loop. J Antimicrob Chemother. 2015 Aug;70(8):2279-86. DOI: 10.1093/jac/dkv094</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkv094</RefLink> </Reference> <Reference refNo="50"> <RefAuthor>Nabarro LE</RefAuthor> <RefAuthor>Veeraraghavan B</RefAuthor> <RefTitle>Combination therapy for carbapenem-resistant Enterobacteriaceae: increasing evidence, unanswered questions, potential solutions</RefTitle> <RefYear>2015</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>2307-11</RefPage> <RefTotal>Nabarro LE, Veeraraghavan B. Combination therapy for carbapenem-resistant Enterobacteriaceae: increasing evidence, unanswered questions, potential solutions. Eur J Clin Microbiol Infect Dis. 2015 Dec;34(12):2307-11. DOI: 10.1007/s10096-015-2486-7</RefTotal> <RefLink>https://doi.org/10.1007/s10096-015-2486-7</RefLink> </Reference> <Reference refNo="51"> <RefAuthor>Nationales Referenzzentrum (NRZ) für gramnegative Krankenhauserreger</RefAuthor> <RefTitle>Bericht des Nationalen Referenzzentrums (NRZ) für gramnegative Krankenhauserreger</RefTitle> <RefYear>2016</RefYear> <RefJournal>Epidemiol Bull</RefJournal> <RefPage>11-4</RefPage> <RefTotal>Nationales Referenzzentrum (NRZ) für gramnegative Krankenhauserreger. Bericht des Nationalen Referenzzentrums (NRZ) für gramnegative Krankenhauserreger. Epidemiol Bull. 2016;(2):11-4. DOI: 10.17886/EpiBull-2016-002</RefTotal> <RefLink>https://doi.org/10.17886/EpiBull-2016-002</RefLink> </Reference> <Reference refNo="52"> <RefAuthor>Daikos GL</RefAuthor> <RefAuthor>Tsaousi S</RefAuthor> <RefAuthor>Tzouvelekis LS</RefAuthor> <RefAuthor>Anyfantis I</RefAuthor> <RefAuthor>Psichogiou M</RefAuthor> <RefAuthor>Argyropoulou A</RefAuthor> <RefAuthor>Stefanou I</RefAuthor> <RefAuthor>Sypsa V</RefAuthor> <RefAuthor>Miriagou V</RefAuthor> <RefAuthor>Nepka M</RefAuthor> <RefAuthor>Georgiadou S</RefAuthor> <RefAuthor>Markogiannakis A</RefAuthor> <RefAuthor>Goukos D</RefAuthor> <RefAuthor>Skoutelis A</RefAuthor> <RefTitle>Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems</RefTitle> <RefYear>2014</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2322-8</RefPage> <RefTotal>Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, Georgiadou S, Markogiannakis A, Goukos D, Skoutelis A. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother. 2014;58(4):2322-8. DOI: 10.1128/AAC.02166-13</RefTotal> <RefLink>https://doi.org/10.1128/AAC.02166-13</RefLink> </Reference> <Reference refNo="53"> <RefAuthor>Tumbarello M</RefAuthor> <RefAuthor>Viale P</RefAuthor> <RefAuthor>Viscoli C</RefAuthor> <RefAuthor>Trecarichi EM</RefAuthor> <RefAuthor>Tumietto F</RefAuthor> <RefAuthor>Marchese A</RefAuthor> <RefAuthor>Spanu T</RefAuthor> <RefAuthor>Ambretti S</RefAuthor> <RefAuthor>Ginocchio F</RefAuthor> <RefAuthor>Cristini F</RefAuthor> <RefAuthor>Losito AR</RefAuthor> <RefAuthor>Tedeschi S</RefAuthor> <RefAuthor>Cauda R</RefAuthor> <RefAuthor>Bassetti M</RefAuthor> <RefTitle>Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy</RefTitle> <RefYear>2012</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>943-50</RefPage> <RefTotal>Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F, Losito AR, Tedeschi S, Cauda R, Bassetti M. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis. 2012 Oct;55(7):943-50. DOI: 10.1093/cid/cis588</RefTotal> <RefLink>https://doi.org/10.1093/cid/cis588</RefLink> </Reference> <Reference refNo="54"> <RefAuthor>Tumbarello M</RefAuthor> <RefAuthor>Trecarichi EM</RefAuthor> <RefAuthor>De Rosa FG</RefAuthor> <RefAuthor>Giannella M</RefAuthor> <RefAuthor>Giacobbe DR</RefAuthor> <RefAuthor>Bassetti M</RefAuthor> <RefAuthor>Losito AR</RefAuthor> <RefAuthor>Bartoletti M</RefAuthor> <RefAuthor>Del Bono V</RefAuthor> <RefAuthor>Corcione S</RefAuthor> <RefAuthor>Maiuro G</RefAuthor> <RefAuthor>Tedeschi S</RefAuthor> <RefAuthor>Celani L</RefAuthor> <RefAuthor>Cardellino CS</RefAuthor> <RefAuthor>Spanu T</RefAuthor> <RefAuthor>Marchese A</RefAuthor> <RefAuthor>Ambretti S</RefAuthor> <RefAuthor>Cauda R</RefAuthor> <RefAuthor>Viscoli C</RefAuthor> <RefAuthor>Viale P</RefAuthor> <RefAuthor> ISGRI-SITA (Italian Study Group on Resistant Infections of the Società Italiana Terapia Antinfettiva)</RefAuthor> <RefTitle>Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study</RefTitle> <RefYear>2015</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>2133-43</RefPage> <RefTotal>Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, Losito AR, Bartoletti M, Del Bono V, Corcione S, Maiuro G, Tedeschi S, Celani L, Cardellino CS, Spanu T, Marchese A, Ambretti S, Cauda R, Viscoli C, Viale P; ISGRI-SITA (Italian Study Group on Resistant Infections of the Società Italiana Terapia Antinfettiva). Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother. 2015 Jul;70(7):2133-43. DOI: 10.1093/jac/dkv086</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkv086</RefLink> </Reference> <Reference refNo="55"> <RefAuthor>Paul M</RefAuthor> <RefAuthor>Carmeli Y</RefAuthor> <RefAuthor>Durante-Mangoni E</RefAuthor> <RefAuthor>Mouton JW</RefAuthor> <RefAuthor>Tacconelli E</RefAuthor> <RefAuthor>Theuretzbacher U</RefAuthor> <RefAuthor>Mussini C</RefAuthor> <RefAuthor>Leibovici L</RefAuthor> <RefTitle>Combination therapy for carbapenem-resistant Gram-negative bacteria</RefTitle> <RefYear>2014</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>2305-9</RefPage> <RefTotal>Paul M, Carmeli Y, Durante-Mangoni E, Mouton JW, Tacconelli E, Theuretzbacher U, Mussini C, Leibovici L. Combination therapy for carbapenem-resistant Gram-negative bacteria. J Antimicrob Chemother. 2014 Sep;69(9):2305-9. DOI: 10.1093/jac/dku168</RefTotal> <RefLink>https://doi.org/10.1093/jac/dku168</RefLink> </Reference> <Reference refNo="56"> <RefAuthor>Bulik CC</RefAuthor> <RefAuthor>Nicolau DP</RefAuthor> <RefTitle>Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae</RefTitle> <RefYear>2011</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>3002-4</RefPage> <RefTotal>Bulik CC, Nicolau DP. Double-carbapenem therapy for carbapenemase-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011 Jun;55(6):3002-4. DOI: 10.1128/AAC.01420-10</RefTotal> <RefLink>https://doi.org/10.1128/AAC.01420-10</RefLink> </Reference> <Reference refNo="57"> <RefAuthor>Giamarellou H</RefAuthor> <RefAuthor>Galani L</RefAuthor> <RefAuthor>Baziaka F</RefAuthor> <RefAuthor>Karaiskos I</RefAuthor> <RefTitle>Effectiveness of a double-carbapenem regimen for infections in humans due to carbapenemase-producing pandrug-resistant Klebsiella pneumoniae</RefTitle> <RefYear>2013</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2388-90</RefPage> <RefTotal>Giamarellou H, Galani L, Baziaka F, Karaiskos I. Effectiveness of a double-carbapenem regimen for infections in humans due to carbapenemase-producing pandrug-resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013 May;57(5):2388-90. DOI: 10.1128/AAC.02399-12</RefTotal> <RefLink>https://doi.org/10.1128/AAC.02399-12</RefLink> </Reference> <Reference refNo="58"> <RefAuthor>Ceccarelli G</RefAuthor> <RefAuthor>Falcone M</RefAuthor> <RefAuthor>Giordano A</RefAuthor> <RefAuthor>Mezzatesta ML</RefAuthor> <RefAuthor>Caio C</RefAuthor> <RefAuthor>Stefani S</RefAuthor> <RefAuthor>Venditti M</RefAuthor> <RefTitle>Successful ertapenem-doripenem combination treatment of bacteremic ventilator-associated pneumonia due to colistin-resistant KPC-producing Klebsiella pneumoniae</RefTitle> <RefYear>2013</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>2900-1</RefPage> <RefTotal>Ceccarelli G, Falcone M, Giordano A, Mezzatesta ML, Caio C, Stefani S, Venditti M. Successful ertapenem-doripenem combination treatment of bacteremic ventilator-associated pneumonia due to colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2013 Jun;57(6):2900-1. DOI: 10.1128/AAC.00188-13</RefTotal> <RefLink>https://doi.org/10.1128/AAC.00188-13</RefLink> </Reference> <Reference refNo="59"> <RefAuthor>Cprek JB</RefAuthor> <RefAuthor>Gallagher JC</RefAuthor> <RefTitle>Ertapenem-Containing Double-Carbapenem Therapy for Treatment of Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae</RefTitle> <RefYear>2015</RefYear> <RefJournal>Antimicrob Agents Chemother</RefJournal> <RefPage>669-73</RefPage> <RefTotal>Cprek JB, Gallagher JC. Ertapenem-Containing Double-Carbapenem Therapy for Treatment of Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae. Antimicrob Agents Chemother. 2015 Nov;60(1):669-73. DOI: 10.1128/AAC.01569-15</RefTotal> <RefLink>https://doi.org/10.1128/AAC.01569-15</RefLink> </Reference> <Reference refNo="60"> <RefAuthor>Pontikis K</RefAuthor> <RefAuthor>Karaiskos I</RefAuthor> <RefAuthor>Bastani S</RefAuthor> <RefAuthor>Dimopoulos G</RefAuthor> <RefAuthor>Kalogirou M</RefAuthor> <RefAuthor>Katsiari M</RefAuthor> <RefAuthor>Oikonomou A</RefAuthor> <RefAuthor>Poulakou G</RefAuthor> <RefAuthor>Roilides E</RefAuthor> <RefAuthor>Giamarellou H</RefAuthor> <RefTitle>Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria</RefTitle> <RefYear>2014</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>52-9</RefPage> <RefTotal>Pontikis K, Karaiskos I, Bastani S, Dimopoulos G, Kalogirou M, Katsiari M, Oikonomou A, Poulakou G, Roilides E, Giamarellou H. Outcomes of critically ill intensive care unit patients treated with fosfomycin for infections due to pandrug-resistant and extensively drug-resistant carbapenemase-producing Gram-negative bacteria. Int J Antimicrob Agents. 2014 Jan;43(1):52-9. DOI: 10.1016/j.ijantimicag.2013.09.010</RefTotal> <RefLink>https://doi.org/10.1016/j.ijantimicag.2013.09.010</RefLink> </Reference> <Reference refNo="63"> <RefAuthor>Shahbazi F</RefAuthor> <RefAuthor>Dashti-Khavidaki S</RefAuthor> <RefTitle>Colistin: efficacy and safety in different populations</RefTitle> <RefYear>2015</RefYear> <RefJournal>Expert Rev Clin Pharmacol</RefJournal> <RefPage>423-48</RefPage> <RefTotal>Shahbazi F, Dashti-Khavidaki S. Colistin: efficacy and safety in different populations. Expert Rev Clin Pharmacol. 2015;8(4):423-48. DOI: 10.1586/17512433.2015.1053390</RefTotal> <RefLink>https://doi.org/10.1586/17512433.2015.1053390</RefLink> </Reference> <Reference refNo="64"> <RefAuthor>Batirel A</RefAuthor> <RefAuthor>Balkan II</RefAuthor> <RefAuthor>Karabay O</RefAuthor> <RefAuthor>Agalar C</RefAuthor> <RefAuthor>Akalin S</RefAuthor> <RefAuthor>Alici O</RefAuthor> <RefAuthor>Alp E</RefAuthor> <RefAuthor>Altay FA</RefAuthor> <RefAuthor>Altin N</RefAuthor> <RefAuthor>Arslan F</RefAuthor> <RefAuthor>Aslan T</RefAuthor> <RefAuthor>Bekiroglu N</RefAuthor> <RefAuthor>Cesur S</RefAuthor> <RefAuthor>Celik AD</RefAuthor> <RefAuthor>Dogan M</RefAuthor> <RefAuthor>Durdu B</RefAuthor> <RefAuthor>Duygu F</RefAuthor> <RefAuthor>Engin A</RefAuthor> <RefAuthor>Engin DO</RefAuthor> <RefAuthor>Gonen I</RefAuthor> <RefAuthor>Guclu E</RefAuthor> <RefAuthor>Guven T</RefAuthor> <RefAuthor>Hatipoglu CA</RefAuthor> <RefAuthor>Hosoglu S</RefAuthor> <RefAuthor>Karahocagil MK</RefAuthor> <RefAuthor>Kilic AU</RefAuthor> <RefAuthor>Ormen B</RefAuthor> <RefAuthor>Ozdemir D</RefAuthor> <RefAuthor>Ozer S</RefAuthor> <RefAuthor>Oztoprak N</RefAuthor> <RefAuthor>Sezak N</RefAuthor> <RefAuthor>Turhan V</RefAuthor> <RefAuthor>Turker N</RefAuthor> <RefAuthor>Yilmaz H</RefAuthor> <RefTitle>Comparison of colistin-carbapenem, colistin-sulbactam, and colistin plus other antibacterial agents for the treatment of extremely drug-resistant Acinetobacter baumannii bloodstream infections</RefTitle> <RefYear>2014</RefYear> <RefJournal>Eur J Clin Microbiol Infect Dis</RefJournal> <RefPage>1311-22</RefPage> <RefTotal>Batirel A, Balkan II, Karabay O, Agalar C, Akalin S, Alici O, Alp E, Altay FA, Altin N, Arslan F, Aslan T, Bekiroglu N, Cesur S, Celik AD, Dogan M, Durdu B, Duygu F, Engin A, Engin DO, Gonen I, Guclu E, Guven T, Hatipoglu CA, Hosoglu S, Karahocagil MK, Kilic AU, Ormen B, Ozdemir D, Ozer S, Oztoprak N, Sezak N, Turhan V, Turker N, Yilmaz H. Comparison of colistin-carbapenem, colistin-sulbactam, and colistin plus other antibacterial agents for the treatment of extremely drug-resistant Acinetobacter baumannii bloodstream infections. Eur J Clin Microbiol Infect Dis. 2014 Aug;33(8):1311-22. DOI: 10.1007/s10096-014-2070-6</RefTotal> <RefLink>https://doi.org/10.1007/s10096-014-2070-6</RefLink> </Reference> <Reference refNo="65"> <RefAuthor>Akova M</RefAuthor> <RefTitle>Sulbactam-containing beta-lactamase inhibitor combinations</RefTitle> <RefYear>2008</RefYear> <RefJournal>Clin Microbiol Infect</RefJournal> <RefPage>185-8</RefPage> <RefTotal>Akova M. Sulbactam-containing beta-lactamase inhibitor combinations. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:185-8. DOI: 10.1111/j.1469-0691.2007.01847.x</RefTotal> <RefLink>https://doi.org/10.1111/j.1469-0691.2007.01847.x</RefLink> </Reference> <Reference refNo="66"> <RefAuthor>Rafailidis PI</RefAuthor> <RefAuthor>Ioannidou EN</RefAuthor> <RefAuthor>Falagas ME</RefAuthor> <RefTitle>Ampicillin/sulbactam: current status in severe bacterial infections</RefTitle> <RefYear>2007</RefYear> <RefJournal>Drugs</RefJournal> <RefPage>1829-49</RefPage> <RefTotal>Rafailidis PI, Ioannidou EN, Falagas ME. Ampicillin/sulbactam: current status in severe bacterial infections. Drugs. 2007;67(13):1829-49. DOI: 10.2165/00003495-200767130-00003</RefTotal> <RefLink>https://doi.org/10.2165/00003495-200767130-00003</RefLink> </Reference> <Reference refNo="67"> <RefAuthor>Rodríguez-Hernández MJ</RefAuthor> <RefAuthor>Cuberos L</RefAuthor> <RefAuthor>Pichardo C</RefAuthor> <RefAuthor>Caballero FJ</RefAuthor> <RefAuthor>Moreno I</RefAuthor> <RefAuthor>Jiménez-Mejías ME</RefAuthor> <RefAuthor>García-Curiel A</RefAuthor> <RefAuthor>Pachón J</RefAuthor> <RefTitle>Sulbactam efficacy in experimental models caused by susceptible and intermediate Acinetobacter baumannii strains</RefTitle> <RefYear>2001</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>479-82</RefPage> <RefTotal>Rodríguez-Hernández MJ, Cuberos L, Pichardo C, Caballero FJ, Moreno I, Jiménez-Mejías ME, García-Curiel A, Pachón J. Sulbactam efficacy in experimental models caused by susceptible and intermediate Acinetobacter baumannii strains. J Antimicrob Chemother. 2001 Apr;47(4):479-82. DOI: 10.1093/jac/47.4.479</RefTotal> <RefLink>https://doi.org/10.1093/jac/47.4.479</RefLink> </Reference> <Reference refNo="68"> <RefAuthor>Betrosian AP</RefAuthor> <RefAuthor>Frantzeskaki F</RefAuthor> <RefAuthor>Xanthaki A</RefAuthor> <RefAuthor>Douzinas EE</RefAuthor> <RefTitle>Efficacy and safety of high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia</RefTitle> <RefYear>2008</RefYear> <RefJournal>J Infect</RefJournal> <RefPage>432-6</RefPage> <RefTotal>Betrosian AP, Frantzeskaki F, Xanthaki A, Douzinas EE. Efficacy and safety of high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia. J Infect. 2008 Jun;56(6):432-6. DOI: 10.1016/j.jinf.2008.04.002</RefTotal> <RefLink>https://doi.org/10.1016/j.jinf.2008.04.002</RefLink> </Reference> <Reference refNo="69"> <RefAuthor>Choi JY</RefAuthor> <RefAuthor>Kim CO</RefAuthor> <RefAuthor>Park YS</RefAuthor> <RefAuthor>Yoon HJ</RefAuthor> <RefAuthor>Shin SY</RefAuthor> <RefAuthor>Kim YK</RefAuthor> <RefAuthor>Kim MS</RefAuthor> <RefAuthor>Kim YA</RefAuthor> <RefAuthor>Song YG</RefAuthor> <RefAuthor>Yong D</RefAuthor> <RefAuthor>Lee K</RefAuthor> <RefAuthor>Kim JM</RefAuthor> <RefTitle>Comparison of efficacy of cefoperazone/sulbactam and imipenem/cilastatin for treatment of Acinetobacter bacteremia</RefTitle> <RefYear>2006</RefYear> <RefJournal>Yonsei Med J</RefJournal> <RefPage>63-9</RefPage> <RefTotal>Choi JY, Kim CO, Park YS, Yoon HJ, Shin SY, Kim YK, Kim MS, Kim YA, Song YG, Yong D, Lee K, Kim JM. Comparison of efficacy of cefoperazone/sulbactam and imipenem/cilastatin for treatment of Acinetobacter bacteremia. Yonsei Med J. 2006 Feb;47(1):63-9. DOI: 10.3349/ymj.2006.47.1.63</RefTotal> <RefLink>https://doi.org/10.3349/ymj.2006.47.1.63</RefLink> </Reference> <Reference refNo="70"> <RefAuthor>Wood GC</RefAuthor> <RefAuthor>Hanes SD</RefAuthor> <RefAuthor>Croce MA</RefAuthor> <RefAuthor>Fabian TC</RefAuthor> <RefAuthor>Boucher BA</RefAuthor> <RefTitle>Comparison of ampicillin-sulbactam and imipenem-cilastatin for the treatment of acinetobacter ventilator-associated pneumonia</RefTitle> <RefYear>2002</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>1425-30</RefPage> <RefTotal>Wood GC, Hanes SD, Croce MA, Fabian TC, Boucher BA. Comparison of ampicillin-sulbactam and imipenem-cilastatin for the treatment of acinetobacter ventilator-associated pneumonia. Clin Infect Dis. 2002 Jun;34(11):1425-30. DOI: 10.1086/340055</RefTotal> <RefLink>https://doi.org/10.1086/340055</RefLink> </Reference> <Reference refNo="71"> <RefAuthor>Oliveira MS</RefAuthor> <RefAuthor>Prado GV</RefAuthor> <RefAuthor>Costa SF</RefAuthor> <RefAuthor>Grinbaum RS</RefAuthor> <RefAuthor>Levin AS</RefAuthor> <RefTitle>Ampicillin/sulbactam compared with polymyxins for the treatment of infections caused by carbapenem-resistant Acinetobacter spp</RefTitle> <RefYear>2008</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>1369-75</RefPage> <RefTotal>Oliveira MS, Prado GV, Costa SF, Grinbaum RS, Levin AS. Ampicillin/sulbactam compared with polymyxins for the treatment of infections caused by carbapenem-resistant Acinetobacter spp. J Antimicrob Chemother. 2008 Jun;61(6):1369-75. DOI: 10.1093/jac/dkn128</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkn128</RefLink> </Reference> <Reference refNo="72"> <RefAuthor>Falagas ME</RefAuthor> <RefAuthor>Vardakas KZ</RefAuthor> <RefAuthor>Kapaskelis A</RefAuthor> <RefAuthor>Triarides NA</RefAuthor> <RefAuthor>Roussos NS</RefAuthor> <RefTitle>Tetracyclines for multidrug-resistant Acinetobacter baumannii infections</RefTitle> <RefYear>2015</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>455-60</RefPage> <RefTotal>Falagas ME, Vardakas KZ, Kapaskelis A, Triarides NA, Roussos NS. Tetracyclines for multidrug-resistant Acinetobacter baumannii infections. Int J Antimicrob Agents. 2015 May;45(5):455-60. DOI: 10.1016/j.ijantimicag.2014.12.031</RefTotal> <RefLink>https://doi.org/10.1016/j.ijantimicag.2014.12.031</RefLink> </Reference> <Reference refNo="73"> <RefAuthor>Karageorgopoulos DE</RefAuthor> <RefAuthor>Kelesidis T</RefAuthor> <RefAuthor>Kelesidis I</RefAuthor> <RefAuthor>Falagas ME</RefAuthor> <RefTitle>Tigecycline for the treatment of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence</RefTitle> <RefYear>2008</RefYear> <RefJournal>J Antimicrob Chemother</RefJournal> <RefPage>45-55</RefPage> <RefTotal>Karageorgopoulos DE, Kelesidis T, Kelesidis I, Falagas ME. Tigecycline for the treatment of multidrug-resistant (including carbapenem-resistant) Acinetobacter infections: a review of the scientific evidence. J Antimicrob Chemother. 2008 Jul;62(1):45-55. DOI: 10.1093/jac/dkn165</RefTotal> <RefLink>https://doi.org/10.1093/jac/dkn165</RefLink> </Reference> <Reference refNo="74"> <RefAuthor>Robert-Koch-Institut</RefAuthor> <RefTitle></RefTitle> <RefYear></RefYear> <RefBookTitle>ARS – Antibiotika-Resistenz-Surveillance</RefBookTitle> <RefPage></RefPage> <RefTotal>Robert-Koch-Institut. ARS – Antibiotika-Resistenz-Surveillance. Datenstand: 22.8.2016. [cited 2017 Feb 13]. Available from: https://ars.rki.de</RefTotal> <RefLink>https://ars.rki.de</RefLink> </Reference> <Reference refNo="75"> <RefAuthor>Arbeitsgemeinschaft „Empfindlichkeitsprüfung und Resistenz“</RefAuthor> <RefTitle></RefTitle> <RefYear></RefYear> <RefBookTitle>Individuelle Datenbankabfrage – PEG-Resistenzstudien 2010 und 2013</RefBookTitle> <RefPage></RefPage> <RefTotal>Arbeitsgemeinschaft „Empfindlichkeitsprüfung und Resistenz“. Individuelle Datenbankabfrage – PEG-Resistenzstudien 2010 und 2013. [cited 2017 Feb 13]. Available from: http://p-e-g.org/resistenz/database/auswertung.php</RefTotal> <RefLink>http://p-e-g.org/resistenz/database/auswertung.php</RefLink> </Reference> <Reference refNo="76"> <RefAuthor>Falagas ME</RefAuthor> <RefAuthor>Vardakas KZ</RefAuthor> <RefAuthor>Roussos NS</RefAuthor> <RefTitle>Trimethoprim/sulfamethoxazole for Acinetobacter spp.: A review of current microbiological and clinical evidence</RefTitle> <RefYear>2015</RefYear> <RefJournal>Int J Antimicrob Agents</RefJournal> <RefPage>231-41</RefPage> <RefTotal>Falagas ME, Vardakas KZ, Roussos NS. Trimethoprim/sulfamethoxazole for Acinetobacter spp.: A review of current microbiological and clinical evidence. Int J Antimicrob Agents. 2015 Sep;46(3):231-41. DOI: 10.1016/j.ijantimicag.2015.04.002</RefTotal> <RefLink>https://doi.org/10.1016/j.ijantimicag.2015.04.002</RefLink> </Reference> <Reference refNo="77"> <RefAuthor>Durante-Mangoni E</RefAuthor> <RefAuthor>Signoriello G</RefAuthor> <RefAuthor>Andini R</RefAuthor> <RefAuthor>Mattei A</RefAuthor> <RefAuthor>De Cristoforo M</RefAuthor> <RefAuthor>Murino P</RefAuthor> <RefAuthor>Bassetti M</RefAuthor> <RefAuthor>Malacarne P</RefAuthor> <RefAuthor>Petrosillo N</RefAuthor> <RefAuthor>Galdieri N</RefAuthor> <RefAuthor>Mocavero P</RefAuthor> <RefAuthor>Corcione A</RefAuthor> <RefAuthor>Viscoli C</RefAuthor> <RefAuthor>Zarrilli R</RefAuthor> <RefAuthor>Gallo C</RefAuthor> <RefAuthor>Utili R</RefAuthor> <RefTitle>Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial</RefTitle> <RefYear>2013</RefYear> <RefJournal>Clin Infect Dis</RefJournal> <RefPage>349-58</RefPage> <RefTotal>Durante-Mangoni E, Signoriello G, Andini R, Mattei A, De Cristoforo M, Murino P, Bassetti M, Malacarne P, Petrosillo N, Galdieri N, Mocavero P, Corcione A, Viscoli C, Zarrilli R, Gallo C, Utili R. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis. 2013 Aug;57(3):349-58. DOI: 10.1093/cid/cit253</RefTotal> <RefLink>https://doi.org/10.1093/cid/cit253</RefLink> </Reference> <Reference refNo="78"> <RefAuthor>Aydemir H</RefAuthor> <RefAuthor>Akduman D</RefAuthor> <RefAuthor>Piskin N</RefAuthor> <RefAuthor>Comert F</RefAuthor> <RefAuthor>Horuz E</RefAuthor> <RefAuthor>Terzi A</RefAuthor> <RefAuthor>Kokturk F</RefAuthor> <RefAuthor>Ornek T</RefAuthor> <RefAuthor>Celebi G</RefAuthor> <RefTitle>Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia</RefTitle> <RefYear>2013</RefYear> <RefJournal>Epidemiol Infect</RefJournal> <RefPage>1214-22</RefPage> <RefTotal>Aydemir H, Akduman D, Piskin N, Comert F, Horuz E, Terzi A, Kokturk F, Ornek T, Celebi G. Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol Infect. 2013 Jun;141(6):1214-22. DOI: 10.1017/S095026881200194X</RefTotal> <RefLink>https://doi.org/10.1017/S095026881200194X</RefLink> </Reference> <Reference refNo="79"> <RefAuthor>Viehman JA</RefAuthor> <RefAuthor>Nguyen MH</RefAuthor> <RefAuthor>Doi Y</RefAuthor> <RefTitle>Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections</RefTitle> <RefYear>2014</RefYear> <RefJournal>Drugs</RefJournal> <RefPage>1315-33</RefPage> <RefTotal>Viehman JA, Nguyen MH, Doi Y. Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections. Drugs. 2014 Aug;74(12):1315-33. DOI: 10.1007/s40265-014-0267-8</RefTotal> <RefLink>https://doi.org/10.1007/s40265-014-0267-8</RefLink> </Reference> <Reference refNo="61"> <RefAuthor>Derendorf H</RefAuthor> <RefAuthor>Heinrichs T</RefAuthor> <RefAuthor>Reimers T</RefAuthor> <RefAuthor>Lebert C</RefAuthor> <RefAuthor>Brinkmann A</RefAuthor> <RefTitle>Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Pharmakokinetik und Pharmakodynamik</RefTitle> <RefYear>2020</RefYear> <RefJournal>GMS Infect Dis</RefJournal> <RefPage>Doc17</RefPage> <RefTotal>Derendorf H, Heinrichs T, Reimers T, Lebert C, Brinkmann A. Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Pharmakokinetik und Pharmakodynamik [Calculated parenteral initial treatment of bacterial infections: Pharmacokinetics and pharmacodynamics]. GMS Infect Dis. 2020;8:Doc17. DOI: 10.3205/id000061</RefTotal> <RefLink>https://doi.org/10.3205/id000061</RefLink> </Reference> <Reference refNo="62"> <RefAuthor>Bodmann KF</RefAuthor> <RefAuthor>Höhl R</RefAuthor> <RefAuthor>Krüger W</RefAuthor> <RefAuthor>Grabein B</RefAuthor> <RefAuthor>Graninger W</RefAuthor> <RefTitle>Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Sepsis</RefTitle> <RefYear>2020</RefYear> <RefJournal>GMS Infect Dis</RefJournal> <RefPage>Doc09</RefPage> <RefTotal>Bodmann KF, Höhl R, Krüger W, Grabein B, Graninger W. Kalkulierte parenterale Initialtherapie bakterieller Infektionen: Sepsis [Calculated parenteral initial treatment of bacterial infections: Sepsis]. GMS Infect Dis. 2020;8:Doc09. DOI: 10.3205/id000053</RefTotal> <RefLink>https://doi.org/10.3205/id000053</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: Aktivität von Beta-Lactamase-Inhibitoren [15]</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 1: Activity of beta-lactamase inhibitors [15]</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: Therapieempfehlungen bei Infektionen durch ESBL-bildende Enterobacteriaceae</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 2: Treatment recommendations for infections with ESBL-producing Enterobacteriaceae</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: Therapieempfehlungen bei Carbapenem-resistenten Enterobacteriaceae</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 3: Treatment recommendations for carbapenem-resistant Enterobacteriaceae</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: Therapieempfehlungen bei Infektionen durch Carbapenem-resistente Acinetobacter baumannii</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 4: Treatment of infections with carbapenem-resistant Acinetobacter baumannii </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: Spezielle Applikationsformen von Colistin</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Table 5: Special application forms of colistin</Mark1></Pgraph></Caption> </Table> <NoOfTables>5</NoOfTables> </Tables> <Figures> <Figure format="png" height="302" width="624"> <MediaNo>1</MediaNo> <MediaID language="de">1de</MediaID> <MediaID language="en">1en</MediaID> <Caption language="de"><Pgraph><Mark1>Abbildung 1: Einteilung der Beta-Lactamasen, nach [48]</Mark1></Pgraph></Caption> <Caption language="en"><Pgraph><Mark1>Figure 1: Classification of beta-lactamases, according to [48]</Mark1></Pgraph></Caption> </Figure> <NoOfPictures>1</NoOfPictures> </Figures> <InlineFigures> <NoOfPictures>0</NoOfPictures> </InlineFigures> <Attachments> <NoOfAttachments>0</NoOfAttachments> </Attachments> </Media> </OrigData> </GmsArticle>