Ultima ratio Last-line-Therapie bei Multiresistenz

Ultima ratioLast-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 2017Amélie Desvars-Larrive 2019

Ultima ratio – Last-line-Therapie

Historie der last line

Zeitraum Problem Antibiotika

1980 – 2000 Betalaktamasen Amoxicillin Clav, Ampicillin SulbCeftaxim, Ceftriaxon, Ceftazidim

2000 – 2015 ESBL Piperacillin Tazobactam, CefepimImipenem Cilastatin, Meropenem

ab 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 EuropePLoS 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 SulbCeftaxim, Ceftriaxon, Ceftazidim

2000 – 2015 ESBL Piperacillin Tazobactam, CefepimImipenem Cilastatin, Meropenem

ab 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 - 2017Pat. 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 SulbCeftaxim, Ceftriaxon, Ceftazidim

2000 – 2015 ESBL Piperacillin Tazobactam, CefepimImipenem Cilastatin, Meropenem

ab 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 altAutobus fliegt 60 m!

Im Detail

Freitag Abend Empirie

Aktuelle Pseudomonas Resistenzen

Antibiotika/Legende sensibel intermediär resistentPiperacillin + 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 TestungenPiperacillin + Tazobactam 0% 0% 100% 236Ceftazidim 3% 26% 71% 236Imipenem 2% 56% 43% 236Meropenem 52% 5% 43% 236Ciprofloxacin 2% 71% 27% 236Amikacin 4% 91% 5% 236Aztreonam 0% 39% 61% 236Cefepim 1% 39% 60% 235Tobramycin 2% 86% 11% 236Ceftolozan/Tazobactam 94% 0% 6% 233Ceftazidim/Avibactam 84% 1% 15% 233

Resistent Cefepim

Antibiotika/Legende sensibel intermediär resistent TestungenPiperacillin + Tazobactam 2% 20% 78% 179Ceftazidim 4% 24% 72% 180Imipenem 2% 48% 50% 180Meropenem 48% 4% 48% 180Ciprofloxacin 3% 63% 34% 180Amikacin 4% 86% 10% 180Aztreonam 1% 29% 70% 180Cefepim 0% 0% 100% 180Colistin 100% 0% 0% 19Fosfomycin 0% 0% 100% 6Tobramycin 4% 85% 11% 180Ceftolozan/Tazobactam 90% 0% 10% 174Ceftazidim/Avibactam 78% 0% 22% 174Meropenem/Vaborbactam 12% 0% 88% 8

CefiderocolIsolate 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 ofGram-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 ofGram-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

• 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-emergentnephrotoxicity

10% (3/29) 56% (9/16)

Motsch J et al..O0427. 28th ECCMID, April 2018, Madrid, Spain

*Outcomes in mMITT Population

Cefiderocol for the Treatment of Adult and Pediatric Patients With CysticFibrosis and Achromobacter xylosoxidans InfectionsNathaniel 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 SulbCeftaxim, Ceftriaxon, Ceftazidim

2000 – 2015 ESBL Piperacillin Tazobactam, CefepimImipenem Cilastatin, Meropenem

ab 2015 Meropenem-Resistenz Ceftolozan Tazobactm, Ceftazidim AvibactamImipenem Cilastatin Relebactam, Meropenem Vaborbactam

ab 2020 Metallo – Betalaktamasen Cefiderocol(Aztreonam Avibactam, Eravacyclin, Plazomicin)

? ? …

EINGANGS-DATUM

ERREGERkeine EUCAST-Werte für Acinetobacter und Pseudomonas!! Carbapenemase

DD-CZA

DD-MEM DD-C/T DD-IPM ET-ATM ET-MeVa

Komb_ CZA-ATM

BewertungKomb_ CZA-

ATM22.02.2019 Klebsiella pneumoniae -4MRGN OXA-48 22 8 22 7 0,38 12 0,1326.07.2017 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 nichtangewachsen

19.06.2019 Klebsiella pneumoniae -4MRGNOXA 48, Gruppe D Carbapenemasen 6 15 <6 15 24 1 syn.Ef syn.Ef

10.04.2017 Enterobacter cloacae -4MRGNNDM (Gr B Metallo-

Betalaktamasen) 7 7 <6 7 128 16 syn.Ef syn.Ef26.06.2017 Klebsiella pneumoniae -4MRGN NDM 6 7 <6 7 128 12 0,25 0,003= S

06.05.2019 Klebsiella pneumoniae -4MRGNKPC (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 =S26.07.2017 Providentia stuartii - 4 MRGN NDM <6 <6 <6 <6 64 >256 syn.Ef syn.Ef26.07.2017 Klebsiella pneumoniae -ESBL- 3MRGN ESBL 19 26 12 24 >256 0,047 syn.Ef syn.Ef26.07.2017 Serratia marcescens-ESBL-3MRGN ESBL 23 27 16 23 48 0,094 syn.Ef syn.Ef

03.08.2017 Klebsiella pneumoniae -4MRGNOXA-48, ESBL (CTX-M1), SHV

und TEM Betalaktamase 19 8 7 9 >256 16 syn.Ef syn.Ef

11.01.2018 Escherichia coli - 4MRGNESBL (CTX-M1)

und OXA-1 Betalaktamase 16 14 7 21 >256 3

leichter komb.Ef

fektleichter

komb.Effekt

29.07.2019 Klebsiella pneumoniae -4MRGN AmpC 10 0 0 13 >256 0,75 32 0,25 = S09.08.2019 Acinetobacter baumannii- 4 MRGN OXA-23, OXA-51 0 0 11 7 32 256 12 1,125= I02.08.2019 Enterobacter cloacae -4MRGN VIM 0 0 0 0 12 >256 0,5 0,04=S18.07.2019 Enterobacter cloacae -4MRGN VIM 0 0 0 0 24 256 1 0,05 = S19.08.2019 Pseudomonas aeruginosa- 4 MRGN - 0 0 17 0 64 256 8 1,125 = I19.08.2019 Pseudomonas aeruginosa- 4 MRGN - 0 0 19 0 64 256 8 0,795 = I12.08.2019 Enterobacter cloacae -4MRGN VIM 0 0 0 0 1 256 0,19 0,19=S08.08.2019 Klebsiella pneumoniae -4MRGN OXA-48 12 0 0 0 >256 256 0,25 0,25 =S21.08.2019 Enterobacter cloacae -4MRGN VIM 0 0 0 0 1,5 256 0,5 0,3 = S26.09.2019 Klebsiella pneumoniae -ESBL- 3MRGN 25 29 0,5 28 32 0,047 0,03 0,17 =S26.09.2019 Pseudomonas aeruginosa- 4 MRGN NDM <6 <6 <6 <6 256 256 32 0,25 = S26.09.2019 Providentia stuartii AmpC, (NDM?) <6 <6 <6 <6 12 16 0,13 0,001 =S26.09.2019 Proteus mirabilis- ESBL- 4 MRGN <6 16 <6 20 256 1,5 0,5 0,004 =S26.09.2019 Klebsiella pneumoniae -4MRGN KPC <6 10 <6 16 256 8 1 0,008 = S31.12.2019 Enterobacter cloacae -4MRGN NDM <6 >32 <6 - 4 3 0,02 S02.01.2020 Enterobacter cloacae -4MRGN NDM 8 4 0,02 S17.01.2020 Pseudomonas aeruginosa- 4 MRGN ? 64 24 8 0,792 = I

Aztreonam & Avibactam

Frau – 60 Jahrekomplizierte Pneumonie mit Empyembildung li. myotone Dystrophie Typ 1, Morbus Curschmann-Steinert

Fetcroja - Stenotrophomonas

Stenotrophomonas maltophiliaKDO 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 SulbCeftaxim, Ceftriaxon, Ceftazidim

2000 – 2015 ESBL Piperacillin Tazobactam, CefepimImipenem Cilastatin, Meropenem

ab 2015 MRGN Ceftolozan Tazobactm, Ceftazidim AvibactamImipenem Cilastatin Relebactam, Meropenem Vaborbactam

ab 2020 Metallo – Betalaktamasen CefiderocolEravacyclin, Plazomicin

? ? …

The end …

Das „letzte“ Antibiotikum wird es nicht geben

William Huffman Stewart Niccolò Machiavelli

Die Zeit ist die Mutter der „Wahrheit“… it is time to close the book …