Ultima ratio Last-line-Therapie bei Multiresistenz - O. Janata
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Ultima ratio Last-line-Therapie bei Multiresistenz O. Janata
Inhalt • Chronologie der last-line-therapy • Aktuelle in vitro Daten • Perspektive • disclosure - supported by SHIONOGI
Zufall Produktion von Antibiotika Resistenz gegen Antibiotika
Lechuguilla Cave, Carlsbad Caverns National Park, New Mexico.
Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, et al. (2012) Antibiotic Resistance Is Prevalent in an Isolated Cave
Microbiome. PLOS ONE 7(4): e34953. https://doi.org/10.1371/journal.pone.0034953
Urban brown rats (Rattus norvegicus) as possible source of multidrug-resistant Enterobacteriaceae and meticillin-resistant Staphylococcus spp., Vienna, Austria, 2016 and 2017 Amélie Desvars-Larrive 2019
Ultima ratio – Last-line-Therapie
Historie der last line
Zeitraum Problem Antibiotika
1980 – 2000 Betalaktamasen Amoxicillin Clav, Ampicillin Sulb
Ceftaxim, Ceftriaxon, Ceftazidim
2000 – 2015 ESBL Piperacillin Tazobactam, Cefepim
Imipenem Cilastatin, Meropenem
ab 2015 MRGN Ceftolozan Tazobactm, Ceftazidim Avibactam
Imipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020 Metallo – Betalaktamasen Cefiderocol
Eravacyclin, Plazomicin
? ? …
Vancomycin
Mississippi Mud
Trends in the estimated number of MRSA and G3CREC bacteremias in the European
region.
de Kraker MEA, Davey PG, Grundmann H, on behalf of the BURDEN study group (2011)
Mortality and Hospital Stay Associated with Resistant Staphylococcus aureus and Escherichia coli Bacteremia: Estimating the
Burden of Antibiotic Resistance in Europe
PLoS Med
third-generation cephalosporin-resistant Escherichia coli (G3CREC)HWI & Intraabdominelle Infekte
Historie der last line
Zeitraum Problem Reserve – Antibiotika
1980 – 2000 Betalaktamasen Amoxicillin Clav, Ampicillin Sulb
Ceftaxim, Ceftriaxon, Ceftazidim
2000 – 2015 ESBL Piperacillin Tazobactam, Cefepim
Imipenem Cilastatin, Meropenem
ab 2015 MRGN Ceftolozan Tazobactm, Ceftazidim Avibactam
Imipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020 Metallo – Betalaktamasen Cefiderocol
Eravacyclin, Plazomicin
? ? …Krankes Kind & resistente Keime
resistente Keime Therapie Harnkultur • Claforan hilft nicht …
Mädchen, 6 Jahre alt perforierte Appendizitis
„gramnegative Stäbchen in der BK“ DSP – empirische Therapie 2010 - 2017 Pat. kommt ins Haus
Trends and correlation between antibacterial consumption and carbapenem resistance in
Gram-negative bacteria
DOI: https://doi.org/10.21203/rs.3.rs-61681/v1Historie der last line
Zeitraum Problem Reserve – Antibiotika
1980 – 2000 Betalaktamasen Amoxicillin Clav, Ampicillin Sulb
Ceftaxim, Ceftriaxon, Ceftazidim
2000 – 2015 ESBL Piperacillin Tazobactam, Cefepim
Imipenem Cilastatin, Meropenem
ab 2015 Meropenem-Resistenz Ceftolozan Tazobactm, Ceftazidim Avibactam
Imipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020 Metallo – Betalaktamasen Cefiderocol
Eravacyclin, Plazomicin
? ? …Zufall Acinetobacter Klebsiella pneumoniae
24.06.2021 Tschechische Republik
Weiblich 15 Jahre alt Autobus fliegt 60 m!
Im Detail
Freitag Abend Empirie
Aktuelle Pseudomonas Resistenzen Geschichte
• Aufn. Wegen Schulterfraktur
Antibiotika/Legende sensibel intermediär resistent
Piperacillin + Tazobactam 2% 51% 47%
Ceftazidim 3% 60% 37%
Imipenem 1% 17% 82% • Harn, BK negativ
Meropenem 0% 0% 100%
Ciprofloxacin 3% 72% 26% • CRP 100 bis 200 ondulierend
Amikacin 4% 90% 6%
Aztreonam 0% 56% 44% • 3 Wochen Meropenem
Cefepim 1% 59% 40%
Tobramycin 4% 86% 10%
Ceftolozan/Tazobactam 93% 0% 7%
• ICU wg. Aspirationspneumonie
Ceftazidim/Avibactam 87% 1% 12%
Cave +/- intermediät = + bei hoher DosisPseudomonas aeruginosa
Resistent PipTaz Resistent Cefepim
Antibiotika/Legende sensibel intermediär resistent Testungen
Piperacillin + Tazobactam 2% 20% 78% 179
Antibiotika/Legende sensibel intermediär resistent Testungen
Ceftazidim 4% 24% 72% 180
Piperacillin + Tazobactam 0% 0% 100% 236
Imipenem 2% 48% 50% 180
Ceftazidim 3% 26% 71% 236
Meropenem 48% 4% 48% 180
Imipenem 2% 56% 43% 236
Ciprofloxacin 3% 63% 34% 180
Meropenem 52% 5% 43% 236
Amikacin 4% 86% 10% 180
Ciprofloxacin 2% 71% 27% 236
Aztreonam 1% 29% 70% 180
Amikacin 4% 91% 5% 236
Cefepim 0% 0% 100% 180
Aztreonam 0% 39% 61% 236
Colistin 100% 0% 0% 19
Cefepim 1% 39% 60% 235
Fosfomycin 0% 0% 100% 6
Tobramycin 2% 86% 11% 236
Tobramycin 4% 85% 11% 180
Ceftolozan/Tazobactam 94% 0% 6% 233
Ceftolozan/Tazobactam 90% 0% 10% 174
Ceftazidim/Avibactam 84% 1% 15% 233
Ceftazidim/Avibactam 78% 0% 22% 174
Meropenem/Vaborbactam 12% 0% 88% 8Cefiderocol Isolate KDO 2020/2021
Nach den Carbapenemen … • Ceftolozan-Tazobactam • Neues Pseudomonas-Cephalosporin • Ceftazidim-Avibactam • Meropenem-Vaborbactam • Neuer Betalaktamase-Hemmer • Imipenem-Relebactam • Cefiderocol • Neues Wirkprinzip
Meropenem-resistente Gramnegative
Substanzen Zulassung
• Meropenem Vaborbactam • Randomisiert vs. Anderes AB
- Vaborem ® - Harnwegsinfekte
- 3 x 2+2 gr - Intraabdominelle Infekte
- Non Inferiorität!
• Imipenem + Cilastatin +
Relebactam - Toxizität!
- Recarbrio ®
- 4 x 0,5+0,5+0,25 • resistente Erreger vs. Best available Tx
- Colistin, …
- Wirksamkeit
- Toxizität
- …Cefiderocol versus high-dose, extended- infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial Richard G Wunderink, et al Lan Infect Dis 2021
Cefiderocol versus high-dose, extended- infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial Richard G Wunderink, et al Lan Infect Dis 2021
RESTORE-IMI-1: Imipenem/Relebactam for
Imipenem-NS GNR
Results
• Imipenem-relebactam was efficacious for imipenem-resistant infections (cUTI, cIAI,
HABP/VABP) and showed significantly lower nephrotoxicity (p=0.002).
• Proportion of subjects with a favorable overall response (mMITT population):
– Imipenem-Relebactam = 71.4%; Colistin + Imipenen = 70.0%
Imipenem- Colistin +
Additional Key Outcomes
Relebactam Imipenem
Favorable Clinical Response
71% (15/21) 40% (4/10)
at day 28*
28-d All-cause mortality* 9.5% (2/21) 30% (3/10)
Treatment-emergent
10% (3/29) 56% (9/16)
nephrotoxicity
*Outcomes in mMITT Population
Motsch J et al..O0427. 28th ECCMID, April 2018, Madrid, SpainCefiderocol for the Treatment of Adult and Pediatric Patients With Cystic Fibrosis and Achromobacter xylosoxidans Infections Nathaniel C. Warner et al in CID 2020
Zulassungsstudien
Zulassungstudien früher jetzt
Historie der last line
Zeitraum Problem Reserve – Antibiotika
1980 – 2000 Betalaktamasen Amoxicillin Clav, Ampicillin Sulb
Ceftaxim, Ceftriaxon, Ceftazidim
2000 – 2015 ESBL Piperacillin Tazobactam, Cefepim
Imipenem Cilastatin, Meropenem
ab 2015 Meropenem-Resistenz Ceftolozan Tazobactm, Ceftazidim Avibactam
Imipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020 Metallo – Betalaktamasen Cefiderocol
(Aztreonam Avibactam, Eravacyclin, Plazomicin)
? ? …Aztreonam & Avibactam
ERREGER Komb_ Bewertung
EINGANGS- keine EUCAST-Werte für Acinetobacter und DD- DD- CZA- Komb_ CZA-
DATUM Pseudomonas!! Carbapenemase CZA MEM DD-C/T DD-IPM ET-ATM ET-MeVa ATM ATM
22.02.2019 Klebsiella pneumoniae -4MRGN OXA-48 22 8 22 7 0,38 12 0,13
26.07.2017 Citrobacter freundii-ESBL- 3MRGN ESBL 29 30 25 25 24 0,032 syn.Ef syn.Ef
11.01.2018 Klebsiella pneumoniae -ESBL- 3MRGN C-ase teste negativ 22 24 16 27 256 0,5 0,19 0,19 = S
angewa
01.03.2019 Klebsiella pneumoniae -4MRGN Gr B Metallo-Betalaktamasen nicht chsen
OXA 48, Gruppe D
19.06.2019 Klebsiella pneumoniae -4MRGN Carbapenemasen 6 15 256 256 0,25 0,25 =S
21.08.2019 Enterobacter cloacae -4MRGN VIM 0 0 0 0 1,5 256 0,5 0,3 = S
26.09.2019 Klebsiella pneumoniae -ESBL- 3MRGN 25 29 0,5 28 32 0,047 0,03 0,17 =S
26.09.2019 Pseudomonas aeruginosa- 4 MRGN NDMFrau – 60 Jahre komplizierte Pneumonie mit Empyembildung li. myotone Dystrophie Typ 1, Morbus Curschmann-Steinert
Fetcroja - Stenotrophomonas
Stenotrophomonas maltophilia
KDO 2021
< < CLSI > >Evolution of Cefiderocol Non-Susceptibility in Pseudomonas aeruginosa in a Patient Without Previous Exposure to the Antibiotic
Historie der last line
Zeitraum Problem Reserve – Antibiotika
1980 – 2000 Betalaktamasen Amoxicillin Clav, Ampicillin Sulb
Ceftaxim, Ceftriaxon, Ceftazidim
2000 – 2015 ESBL Piperacillin Tazobactam, Cefepim
Imipenem Cilastatin, Meropenem
ab 2015 MRGN Ceftolozan Tazobactm, Ceftazidim Avibactam
Imipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020 Metallo – Betalaktamasen Cefiderocol
Eravacyclin, Plazomicin
? ? …The end …
Das „letzte“ Antibiotikum wird es nicht geben
William Huffman Stewart Niccolò Machiavelli
… it is time to close the book … Die Zeit ist die Mutter der „Wahrheit“You can also read
