Neue Antibiotika für die Therapie von multiresistenten gramnegativen Bakterien

Zusammenfassung

Die stetige Zunahme an bakteriellen Resistenzen und von multiresistenten Erregern (MRE) – vor allem im gramnegativen Bereich – ist ein weltweites Problem. Die Entwicklung neuer Wirkstoffe gegen Infektionen mit multiresistenten gramnegativen Erregern (MRGN) besitzt daher höchste Priorität. Im Folgenden werden kürzlich zugelassene oder in der fortgeschrittenen klinischen Prüfung befindliche Antibiotika mit Wirksamkeit gegen MRGN vorgestellt.

Abstract

New β-lactam/β-lactamase inhibitor (BLI) combinations (ceftolozan/tazobactam, ceftazidim/avibactam, meropenem/vaborbactam, imipenem/relebactam, aztreonam/avibactam) are the focus of newly approved antibiotics or those currently in advanced clinical testing. In contrast to the BLI currently available, the new inhibitors avibactam, vaborbactam and relebactam are not structurally β-lactams.

The combination with a BLI protects β-lactam from degradation by broad-spectrum β-lactamases from gram-negative pathogens. The main indications for the new substances are therefore infections with multi-resistant gram-negative bacteria.

In clinical use, it should be noted that the BLI does not close efficacy gaps in the β-lactam/BLI combination (e.g. no effect of cephalosporin/BLI combinations on anaerobes or enterococci).

Cefiderocol is the first representative of the siderophore cephalosporin antibiotic group to enter phase II clinical testing.

Eravacyclin (tetracycline derivative) and plazomicin (aminoglycoside) are new non-β-lactam antibiotics in advanced clinical testing (phase III).

In order to maintain the efficacy of new reserve antibiotics for as long as possible, a prescription should only be made if an additional benefit in comparison to established substances has been proven, e.g. by a resistance test.

Kernaussagen

• Der Schwerpunkt der neu zugelassenen bzw. in der fortgeschrittenen klinischen Prüfung befindlichen Antibiotika sind neue β-Laktam/β-Laktamase-Inhibitor-Kombinationen (Ceftolozan/Tazobactam, Ceftazidim/Avibactam, Meropenem/Vaborbactam, Imipenem/Relebactam, Aztreonam/Avibactam).

• Im Gegensatz zu den bisher verfügbaren β-Laktamase-Inhibitoren (BLI) sind die neuen Inhibitoren Avibactam, Vaborbactam und Relebactam strukturell keine β-Laktame.

• Durch die Kombination mit einem BLI wird das β-Laktam vor dem Abbau durch Breitspektrum-β-Laktamasen von gramnegativen Erregern geschützt. Der Indikationsschwerpunkt der neuen Substanzen sind daher Infektionen mit multiresistenten gramnegativen Bakterien.

• Bei der klinischen Anwendung ist zu berücksichtigen, dass generelle Wirklücken des in den β-Laktam/BLI-Kombinationen enthaltenen β-Laktams durch den BLI nicht geschlossen werden (z. B. keine Wirkung von Cephalosporin/BLI-Kombinationen auf Anaerobier oder Enterokokken).

• Cefiderocol befindet sich als erster Vertreter der Antibiotikagruppe der Siderophor-Cephalosporine in der Phase II der klinischen Prüfung.

• Neue Nicht-β-Laktam-Antibiotika in der fortgeschrittenen klinischen Prüfung (Phase III) sind Eravacyclin (Tetrazyklinderivat) und Plazomicin (Aminoglykosid).

• Um die Wirksamkeit neuer Reserveantibiotika möglichst lange zu erhalten, sollten sie nur verordnet werden, wenn ein Zusatznutzen im Vergleich zu etablierten Substanzen belegt wurde, z. B. durch eine Resistenztestung.

Schlüsselwörter

Antibiotika - multiresistente gramnegative Bakterien - β-Laktam-Antibiotika - β-Laktamase-Inhibitoren

Key words

antibiotics - highly resistant gram-negative bacteria - beta-lactam antibiotics - beta-lactamase inhibitors

• Literatur

• 1 World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. 02/2017 Im Internet: http://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf Stand: 25.04.2018
• 2 Zilberberg MD, Nathanson BH, Sulham K. et al. Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with Enterobacteriaceae urinary tract infection, pneumonia and sepsis. BMC Infect Dis 2017; 17: 279-292
• 3 Maechler F, Peña Diaz LA, Schröder C. et al. Prevalence of carbapenem-resistant organisms and other Gram-negative MDRO in German ICUs: first results from the national nosocomial infection surveillance system (KISS). Infection 2015; 43: 163-168
• 4 Nationales Referenzzentrum für Surveillance von nosokomialen Infektionen (NRZ). KISS Krankenhaus-Infektions-Surveillance-System. Erreger-Surveillance im Modul ITS-KISS. Berechnungszeitraum: Januar 2013 bis Dezember 2016. Im Internet: http://www.nrz-hygiene.de/fileadmin/nrz/module/its/mre/201301_201612_ITS_ALL_MRECDADRef.pdf Stand: 25.04.2018
• 5 Mathers AJ, Peirano G, Pitout JD. The role of epidemic resistance plasmids and international high risk clones in the spread of multidrug-resistant Enterobacteriaceae. Clin Microbiol Rev 2015; 28: 565-591
• 6 Giancola SE, Mahoney MV, Bias TE. et al. Critical evaluation of ceftolozane-tazobactam for complicated urinary tract and intra-abdominal infections. Ther Clin Risk Manag 2016; 12: 787-797
• 7 Huntington JA, Sakoulas G, Umeh O. et al. Efficacy of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTIs) caused by levofloxacin resistant pathogens: results from the ASPECT-cUTI trial. J Antimicrob Chemother 2016; 71: 2014-2021
• 8 Dobias J, Dénervaud-Tendon V, Poirel L. et al. Activity of the novel siderophore cephalosporin cefiderocol against multidrug-resistant Gram-negative pathogens. Eur J Clin Microbiol Infect Dis 2017; 36: 2319-2327
• 9 Monogue ML, Tsuji M, Yamano Y. et al. Efficacy of humanized exposures of Cefiderocol (S-649266) against a diverse population of Gram-negative bacteria in the murine thigh infection model. Antimicrob Agents Chemother 2017; 61: pii:e01022-17
• 10 Portsmouth S, van Veenhuyzen D, Echols R. et al. Clinical response of Cefiderocol compared with Imipenem/Cilastatin in the treatment of adults with complicated urinary tract infections with or without pyelonephritis or acute uncomplicated pyelonephritis: results from a multicenter, double-blind, randomized study (APEKS-cUTI). Open Forum Infect Dis 2017; 4 (Suppl. 01) S537-S538 doi:10.1093/ofid/ofx163.1399
• 11 de Jonge BL, Karlowsky JA, Kazmierczak KM. et al. In vitro susceptibility to Ceftazidime-Avibactam of Carbapenem nonsusceptible Enterobacteriaceae isolates collected during the INFORM Global Surveillance Study (2012 to 2014). Antimicrob Agents Chemother 2016; 60: 3163-3169
• 12 Wagenlehner FM, Sobel JD, Newell P. et al. Ceftazidime-avibactam versus Doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis 2016; 63: 754-762
• 13 Vasoo S, Cunningham SA, Cole NC. et al. In vitro activities of Ceftazidime-Avibactam, Aztreonam-Avibactam, and a panel of older and contemporary antimicrobial agents against carbapenemase-producing Gram-negative bacilli. Antimicrob Agents Chemother 2015; 59: 7842-7846
• 14 Karlowsky JA, Kazmierczak KM, de Jonge BLM. et al. In vitro activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas aeruginosa isolated by clinical laboratories in 40 countries from 2012 to 2015. Antimicrob Agents Chemother 2017; 61: e00472-17 doi:10.1128/AAC.00472-17
• 15 Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence 2017; 8: 403-416
• 16 Lomovskaya O, Sun D, Rubio-Aparicio D. et al. Vaborbactam: spectrum of Beta-Lactamase inhibition and impact of resistance mechanisms on activity in Enterobacteriaceae. Antimicrob Agents Chemother 2017; 61: e01443-17 doi:10.1128/AAC.01443-17
• 17 Lapuebla A, Abdallah W, Olafisoye O. et al. Activity of Meropenem combined with RPX7009, a novel β-Lactamase Inhibitor, against Gram-negative clinical isolates. Antimicrob Agents Chemother 2015; 59: 4856-4860
• 18 Castanheira M, Huband MD, Mendes RE. et al. Meropenem-Vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including Carbapenem-resistant, KPC-producing, multidrug-resistant, and extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother 2017; 61: e00567-17 doi:10.1128/AAC.00567-17
• 19 Solomkin J, Evans D, Slepavicius A. et al. Assessing the efficacy and safety of Eravacycline vs. Ertapenem in complicated intra-abdominal infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) Trial: a randomized clinical trial. JAMA Surgery 2017; 152: 224-232
• 20 Haidar G, Alkroud A, Cheng S. et al. Association between the presence of Aminoglycoside-modifying enzymes and in vitro activity of Gentamicin, Tobramycin, Amikacin, and Plazomicin against Klebsiella pneumoniae Carbapenemase- and Extended-Spectrum-β-Lactamase-producing Enterobacter species. Antimicrob Agents Chemother 2016; 60: 5208-5214
• 21 Cloutier DJ, Miller LG, Komirenko AS. et al. Plazomicin Versus Meropenem for the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis: Results of the EPIC Study. 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Vienna, Austria, April 22–25, 2017. Im Internet: http://www.achaogen.com/s/ECCMID-17-EPIC_Final.pdf Stand: 25.04.2018