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, Ceftazidim2000 – 2015
ESBL Piperacillin Tazobactam, Cefepim Imipenem Cilastatin, Meropenemab 2015
MRGN Ceftolozan Tazobactm, Ceftazidim AvibactamImipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020
Metallo – Betalaktamasen CefiderocolEravacyclin, 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-resistantEscherichia coli(G3CREC)
HWI & Intraabdominelle Infekte
Historie der last line
Zeitraum Problem Reserve – Antibiotika
1980 – 2000
Betalaktamasen Amoxicillin Clav, Ampicillin Sulb Ceftaxim, Ceftriaxon, Ceftazidim2000 – 2015
ESBL Piperacillin Tazobactam, Cefepim Imipenem Cilastatin, Meropenemab 2015
MRGN Ceftolozan Tazobactm, Ceftazidim AvibactamImipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020
Metallo – Betalaktamasen CefiderocolEravacyclin, Plazomicin
?
? …Krankes Kind & resistente Keime
resistente Keime
Therapie
• Claforan hilft nicht … Harnkultur
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/v1
Historie der last line
Zeitraum Problem Reserve – Antibiotika
1980 – 2000
Betalaktamasen Amoxicillin Clav, Ampicillin Sulb Ceftaxim, Ceftriaxon, Ceftazidim2000 – 2015
ESBL Piperacillin Tazobactam, Cefepim Imipenem Cilastatin, Meropenemab 2015
Meropenem-Resistenz Ceftolozan Tazobactm, Ceftazidim AvibactamImipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020
Metallo – Betalaktamasen CefiderocolEravacyclin, 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
Antibiotika/Legende sensibel intermediär resistent
Piperacillin + Tazobactam 2% 51% 47%
Ceftazidim 3% 60% 37%
Imipenem 1% 17% 82%
Meropenem 0% 0% 100%
Ciprofloxacin 3% 72% 26%
Amikacin 4% 90% 6%
Aztreonam 0% 56% 44%
Cefepim 1% 59% 40%
Tobramycin 4% 86% 10%
Ceftolozan/Tazobactam 93% 0% 7%
Ceftazidim/Avibactam 87% 1% 12%
Geschichte
• Aufn. Wegen Schulterfraktur
• Harn, BK negativ
• CRP 100 bis 200 ondulierend
• 3 Wochen Meropenem
• ICU wg. Aspirationspneumonie
Cave +/- intermediät = + bei hoher Dosis
Pseudomonas aeruginosa
Resistent PipTaz
Antibiotika/Legende sensibel intermediär resistent Testungen
Piperacillin + Tazobactam 0% 0% 100% 236
Ceftazidim 3% 26% 71% 236
Imipenem 2% 56% 43% 236
Meropenem 52% 5% 43% 236
Ciprofloxacin 2% 71% 27% 236
Amikacin 4% 91% 5% 236
Aztreonam 0% 39% 61% 236
Cefepim 1% 39% 60% 235
Tobramycin 2% 86% 11% 236
Ceftolozan/Tazobactam 94% 0% 6% 233
Ceftazidim/Avibactam 84% 1% 15% 233
Resistent Cefepim
Antibiotika/Legende sensibel intermediär resistent Testungen
Piperacillin + Tazobactam 2% 20% 78% 179
Ceftazidim 4% 24% 72% 180
Imipenem 2% 48% 50% 180
Meropenem 48% 4% 48% 180
Ciprofloxacin 3% 63% 34% 180
Amikacin 4% 86% 10% 180
Aztreonam 1% 29% 70% 180
Cefepim 0% 0% 100% 180
Colistin 100% 0% 0% 19
Fosfomycin 0% 0% 100% 6
Tobramycin 4% 85% 11% 180
Ceftolozan/Tazobactam 90% 0% 10% 174
Ceftazidim/Avibactam 78% 0% 22% 174
Meropenem/Vaborbactam 12% 0% 88% 8
Cefiderocol
Isolate KDO 2020/2021
Nach den Carbapenemen …
• Ceftolozan-Tazobactam
• Ceftazidim-Avibactam
• Meropenem-Vaborbactam
• Imipenem-Relebactam
• Cefiderocol
• Neues Pseudomonas-Cephalosporin
• Neuer Betalaktamase-Hemmer
• Neues Wirkprinzip
Meropenem-resistente Gramnegative
Substanzen
• Meropenem Vaborbactam
- Vaborem ® - 3 x 2+2 gr
• Imipenem + Cilastatin + Relebactam
- Recarbrio ®
- 4 x 0,5+0,5+0,25
Zulassung
• Randomisiert vs. Anderes AB
- Harnwegsinfekte
- Intraabdominelle Infekte
- Non Inferiorität!
- Toxizität!
• 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 2021Cefiderocol 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 2021RESTORE-IMI-1: Imipenem/Relebactam for Imipenem-NS GNR
• 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%
Results
Additional Key Outcomes Imipenem- Relebactam
Colistin + Imipenem Favorable Clinical Response
at day 28* 71% (15/21) 40% (4/10)
28-d All-cause mortality* 9.5% (2/21) 30% (3/10) Treatment-emergent
nephrotoxicity 10% (3/29) 56% (9/16)
Motsch J et al..O0427. 28thECCMID, April 2018, Madrid, Spain
*Outcomes in mMITT Population
Cefiderocol 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, Ceftazidim2000 – 2015
ESBL Piperacillin Tazobactam, Cefepim Imipenem Cilastatin, Meropenemab 2015
Meropenem-Resistenz Ceftolozan Tazobactm, Ceftazidim AvibactamImipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020
Metallo – Betalaktamasen Cefiderocol(Aztreonam Avibactam, Eravacyclin, Plazomicin)
?
? …EINGANGS- DATUM
ERREGER
keine EUCAST-Werte für Acinetobacter und
Pseudomonas!! Carbapenemase CZADD- DD-
MEM DD-C/T DD-IPM ET-ATM ET-MeVa Komb_
CZA- ATM
Bewertung Komb_ CZA-
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
01.03.2019 Klebsiella pneumoniae -4MRGN Gr B Metallo-Betalaktamasen nicht angewa
chsen 19.06.2019 Klebsiella pneumoniae -4MRGN OXA 48, Gruppe D
Carbapenemasen 6 15 <6 15 24 1 syn.Ef syn.Ef
10.04.2017 Enterobacter cloacae -4MRGN
NDM (Gr B Metallo-
Betalaktamasen) 7 7 <6 7 128 16 syn.Ef syn.Ef
26.06.2017 Klebsiella pneumoniae -4MRGN NDM 6 7 <6 7 128 12 0,25 0,003= S
06.05.2019 Klebsiella pneumoniae -4MRGN
KPC (Gr A Carbapenemasen),
SHV und TEM Betalaktamase 18 16 6 12 >256 0,047 0,19 0,127 = S
08.03.2019 Enterobacter cloacae -4MRGN VIM 7 16 <6 14 1 0,38 0,09 0,095 =S
26.07.2017 Providentia stuartii - 4 MRGN NDM <6 <6 <6 <6 64 >256 syn.Ef syn.Ef
26.07.2017 Klebsiella pneumoniae -ESBL- 3MRGN ESBL 19 26 12 24 >256 0,047 syn.Ef syn.Ef
26.07.2017 Serratia marcescens-ESBL-3MRGN ESBL 23 27 16 23 48 0,094 syn.Ef syn.Ef
03.08.2017 Klebsiella pneumoniae -4MRGN
OXA-48, ESBL (CTX-M1), SHV
und TEM Betalaktamase 19 8 7 9 >256 16 syn.Ef syn.Ef
11.01.2018 Escherichia coli - 4MRGN
ESBL (CTX-M1)
und OXA-1 Betalaktamase 16 14 7 21 >256 3
leichter komb.Ef fekt
leichter komb.Effekt
29.07.2019 Klebsiella pneumoniae -4MRGN AmpC 10 0 0 13 >256 0,75 32 0,25 = S
09.08.2019 Acinetobacter baumannii- 4 MRGN OXA-23, OXA-51 0 0 11 7 32 256 12 1,125= I
02.08.2019 Enterobacter cloacae -4MRGN VIM 0 0 0 0 12 >256 0,5 0,04=S
18.07.2019 Enterobacter cloacae -4MRGN VIM 0 0 0 0 24 256 1 0,05 = S
19.08.2019 Pseudomonas aeruginosa- 4 MRGN - 0 0 17 0 64 256 8 1,125 = I
19.08.2019 Pseudomonas aeruginosa- 4 MRGN - 0 0 19 0 64 256 8 0,795 = I
12.08.2019 Enterobacter cloacae -4MRGN VIM 0 0 0 0 1 256 0,19 0,19=S
08.08.2019 Klebsiella pneumoniae -4MRGN OXA-48 12 0 0 0 >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 NDM <6 <6 <6 <6 256 256 32 0,25 = S
26.09.2019 Providentia stuartii AmpC, (NDM?) <6 <6 <6 <6 12 16 0,13 0,001 =S
26.09.2019 Proteus mirabilis- ESBL- 4 MRGN <6 16 <6 20 256 1,5 0,5 0,004 =S
26.09.2019 Klebsiella pneumoniae -4MRGN KPC <6 10 <6 16 256 8 1 0,008 = S
31.12.2019 Enterobacter cloacae -4MRGN NDM <6 >32 <6 - 4 3 0,02 S
02.01.2020 Enterobacter cloacae -4MRGN NDM 8 4 0,02 S
17.01.2020 Pseudomonas aeruginosa- 4 MRGN ? 64 24 8 0,792 = I
Aztreonam & Avibactam
Frau – 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, Ceftazidim2000 – 2015
ESBL Piperacillin Tazobactam, Cefepim Imipenem Cilastatin, Meropenemab 2015
MRGN Ceftolozan Tazobactm, Ceftazidim AvibactamImipenem Cilastatin Relebactam, Meropenem Vaborbactam
ab 2020
Metallo – Betalaktamasen CefiderocolEravacyclin, Plazomicin
?
? …The end …