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Home , Cefiderocol, Cefonicid, Haemophilus influenzae, Vaborbactam

What’s really new in therapy?

Martin J. Hug Freiburg University Medical Center

EAHP Academy Seminars 20-21 September 2019 Newsweek, May 24-31 2019 Disclosures

There are no conflicts of interest to declare

EAHP Academy Seminars 20-21 September 2019 Antiinfectives and Resistance

EAHP Academy Seminars 20-21 September 2019 Resistance of to Pip.-Taz.

olates)

EAHP Academy Seminars 20-21 September 2019 https://resistancemap.cddep.org/AntibioticResistance.php Multiresistant Combined resistance against at least three different types of , 2017

EAHP Academy Seminars 20-21 September 2019 https://atlas.ecdc.europa.eu/public/index.aspx Distribution of ESBL producing

EAHP Academy Seminars 20-21 September 2019

Rossolini GM. Global threat of Gram-negative . 27th ECCMID, Vienna, 2017, IS07 Priority Defined by the World Health Organisation

Critical Priority High Priority Medium Priority Acinetobacter baumanii Enterococcus faecium -resistant -resistant -non-susceptible Pseudomonas aeruginosa influenzae carbapenem-resistant -resistant -resistant Enterobacteriaceae Salmonella species Shigella species carbapenem-resistant fluoroquinolone-resistant fluoroquinolone-resistant vancomycin or -resistant Campylobacter species fluoroquinolone-resistant Neisseria gonorrhoae 3rd gen. -resistant fluoroquinolone-resistant

EAHP Academy Seminars 20-21 September 2019 Data taken from: https://www.who.int/foodsafety/publications/antimicrobials-sixth/en/ Antibacterial Targets

EAHP Academy Seminars 20-21 September 2019 Resistance mechanisms

EAHP Academy Seminars 20-21 September 2019 Mukerji S et al. Essays In Biochemistry 2017, 61(1) 23-35 Veterinary and Human use of Antibiotics Them or us?

Aminoglycosides Glycopeptides Diaminopyridines Lipopeptides Fluoroquinolones Lincosamides Oxazolidinones Pleuromutilins Streptogramins Phenicoles Sulfonamides Tetracyclins

EAHP Academy Seminars 20-21 September 2019 Data taken from: https://www.bvl.bund.de/SharedDocs/Downloads/ 07_Bundesamt/Veranstaltungen/Symposium2013/symposium2013_vortrag_wallmann.pdf Use Density of Critically Important Antibiotics in German Hospitals Data: ADKA if DGI antibiotic surveillance project 2,5 Vancomycin + Cilastatin 2 Tigecyclin Other 1,5

1 RDD/100 Pt. Days 0,5

0 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 EAHP Academy Seminars 20-21 September 2019 Use Density of Novel Cephalosporins in German Hospitals Data: ADKA if DGI antibiotic surveillance project

0,04 Sum Ceftazidim + Ceftolozan + 0,03 Ceftarolin

0,02

RDD/100 Pt. Days 0,01

0 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 EAHP Academy Seminars 20-21 September 2019 Development Pipeline of Antibiotic Drugs

16

14

12

10

8

Count 6

4

2

0 Phase 1 Phase 2 Phase 3 New drug Approved application EAHP Academy Seminars 20-21 September 2019 Data: https://www.pewtrusts.org/-/media/assets/2019/03/antibiotics-currently-in-global-clinical-development.pdf Novel Antibiotics (a selection)

• Long acting Glycopeptides • ß-lactams • ß-lactams + ß-lactam inhibitors • Pleuromutilines • LpxC Inhibitors • Bacteriophages • Fecal Microbiome Transfer

EAHP Academy Seminars 20-21 September 2019 Antiinfective drugs – already FDA / EMA approved

Gram-positive Gram-negative bacteria (DalvanceTM/ Xydalba®) CEFTOBIPROL (Zevtera®) CEFTOLOZAN-TAZOBACTAM (OrbactivTM) (ZerbaxaTM) ® TEDIZOLID (Sivextro ) CEFTAZIDIM-AVIBACTAM CEFTOBIPROL (Zevtera®) (AvycazTM/ Zavicefta®) EAHP Academy Seminars 20-21 September 2019 Antibacterial Targets Inhibitors of assembly

*

*Glycopeptides

EAHP Academy Seminars 20-21 September 2019 Novel Approved Antiinfectives: Glycopeptides

Vancomycin Dalbavancin Oritavancin

EAHP Academy Seminars 20-21 September 2019 Clinical response to Dalbavancin Acute bacterial skin and skin-structure 100 90 n = 573 n = 836 Dalbavancin 0,5g 1x day 1 80 and day 8 70 Vancomycin 2x1g /

patients 60 Linezolid 2x600 mg daily

of 50 40 30 20 10 Percentage 0 Outcome DISCOVER 1 Outcome DISCOVER 2 Side effects DISCOVER 1 EAHP Academy Seminars 20-21 September 2019 Data taken from: Boucher H et al. N Engl J Med 2014;370:2169-79 Clinical response to Oritavancin Acute bacterial skin and skin-structure infection 100 n = 791 Oritavancin 1,2g 1x 90 Single Shot 80 70 Vancomycin 2x1g patients 60 daily for 7-10 days of 50 n = 591 40 30 20

Percentage 10 0 Primary endpoint Secondary endpoint Tertiary endpoint Side effects EAHP Academy Seminars 20-21 September 2019 Data: Corey CG et al. N Engl J Med 2014;370:2180-90 Take Home Message

• Dalbavancin and Oritavancin are novel Glycopeptide antibiotics to treat caused by gram-positive bacteria. • Oritavancin and Dalbavancin have an apparent half-life of 10 – 15 days respectively, which permits a single dosing regime. • Both substances are aproved for the treatment of acute bacterial skin, skin- structure and soft tissue infections. • To this end no data exist to demonstrate a clinical benefit compared to established Glycopeptides other than better treatment options in the outpatient sector.

EAHP Academy Seminars 20-21 September 2019 Antibacterial Targets Inhibitors of cell wall assembly *

*Cephalosporins

EAHP Academy Seminars 20-21 September 2019 Novel Antiinfectives: Cephalosporins (O) = oral use 1st Generation 2nd Generation 3rd Generation 4th Generation Cephalothin (O) (-axetil (O)) Cephalexin (O) (O) Cephradine (O) (O) (O) Moxalactam (O) (O) (O) 5th Generation (O) Ceftarolin Ceftibuten (O) Ceftobiprol EAHP Academy Seminars 20-21 September 2019 – same same but different Ceftazidime Cefepime

Cefiderocol 3+ Fe EAHP Academy Seminars 20-21 September 2019 Porin Specific Entry of Cefiderocol

Fe3+ Fe3+ Transporter

EAHP Academy Seminars 20-21 September 2019 Uptake of Cefiderocol in -depleted Conditions Cefiderocol uptake into P. aeruginosa cells was >2 times higher under low iron conditions 100

80 Iron-depleted conditions (SD) Iron-rich conditions 625

60 /0.1 of OD 40 pmol

20 Uptake,

0

0 5 10

OD, optical density; SD, standard deviation Time, min EAHP Academy Seminars 20-21 September 2019 Ito A, et al. Antimicrob Agents Chemother 2016;60:7396–401 Cefiderocol in Complicated Urinary Tract Infections Trial design Patients assesed for eligibility: n=495

RandomisedExcluded: n:=43 n=452

Imipenem-cilastatin: n=149 Cefiderocol: n=303

Completed in ITT population: n=242 Completed in ITT population: n=249

Endpoints: 1. clinical and microbiological response; 2. safety, clinical and microbiological response at early assessment EAHP Academy Seminars 20-21 September 2019 Mod. from Portsmouth S et al. Lancet Infect Dis. 2018(12):1319-1328 Cefiderocol in Complicated Urinary Tract Infections Distribution of pathogens isolated at baseline

EAHP Academy Seminars 20-21 September 2019 Mod. from Portsmouth S et al. Lancet Infect Dis. 2018(12):1319-1328 Cefiderocol in Complicated Urinary Tract Infections Results

EAHP Academy Seminars 20-21 September 2019 Mod. from Portsmouth S et al. Lancet Infect Dis. 2018(12):1319-1328 Novel Antiinfectives: Combination of Cephalosporines with ß-Lactamase Inhibitors Tazobactam Avibactam

Ceftolozan Ceftazidime

EAHP Academy Seminars 20-21 September 2019 Susceptibility of Different Carbapenem-resistant Pseudomonas Strains in Spain CXA-101 = Ceftolozan CAZ = Ceftazidime FEP = Cefepime

EAHP Academy Seminars 20-21 September 2019 Juan C et al. Antimicrob. Agents Chemother. 2010;54:846-851 Clinical Response to Ceftolozan-Tazobactam Acute abdominal infections 100 90 Ceftolozan 1g+Tazobactam 80 0,5g+Metronidazol 0,5g 70 Meropenem 0,5g patients 60

of 3 x daily each 50 40 30 20 10 Percentage 0 Primary endpoint Secondary endpoint Side effects EAHP Academy Seminars 20-21 September 2019 Data from: Solomkin J et al. Clin Infect Dis 2015;60(10):1462–71 Novel Antiinfectives: Combination of Cephalosporines with ß-Lactamase Inhibitors Sulbactam Tazobactam Avibactam

Ceftolozan Ceftazidime

EAHP Academy Seminars 20-21 September 2019 Clinical Response to Ceftazidime-Avibactam Acute abdominal infections 100 Ceftazidime 2g+Avibactam 90 0.5g+Metronidazol 0.5g 80 Meropenem 0.5g 70 patients 60 of 50 40 30 20 10 Percentage 0 All bacteria Gramnegative Side effects EAHP Academy Seminars 20-21 September 2019 Data from: Lucasti C et al. J Antimicrob Chemother 2013; 68: 1183–1192 Clinical Response to Ceftazidime-Avibactam Complicated urinary tract infections 100 Ceftazidime 2g+Avibactam 0,5g 3x daily 90 80 Imipenem/Cilastatin 0,5g 4x daily 70 patients 60 of 50 40 30 20 10 Percentage 0 All bacteria Gramnegative Side effects EAHP Academy Seminars 20-21 September 2019 Data from: Vasquez JA et al. Curr Med Res Opin. 2012;28(12):1921-31 Combinations of ß-lactams and BLI Ongoing Clinical Trials Vabor- Avibactam Nacubactam Zidebactam bactam Diazabi- Diazabi- Diazabi- Cyclic Diazabi- cyclooctane cyclooctane cyclooctane boronate cyclooctane X* Cefepime X Imipenem- X Cilastatin Meropenem X X* *FDA approved EAHP Academy Seminars 20-21 September 2019 Combinations of ß-lactams and BLI Ongoing Clinical Trials – early development AAI-101 ETX0282 ETX2514 VNRX-5133 Diazabicyclo- Diazabicyclo- Cyclic ß-lactame octane octane boronate Cefepime X X Cefpodoxime- X proxetil Imipenem- X Cilastatin Sulbactam X

EAHP Academy Seminars 20-21 September 2019 Targeting Antibiotic Non-susceptible Gram-negative Organisms (TANGO) Trial – Meropenem+ Trial design Patients assesed for eligibility: n=595

RandomisedExcluded: n:=43 n=550

Piperacillin-tazobactam: n=276 Meropenem-vaborbactam: n=274

Included in analysis: n=178 Included in analysis: n=178

Endpoints: 1. clinical and microbiological response; 2. safety & tolerability

EAHP Academy Seminars 20-21 September 2019 Mod. From: Kaye KS et al. JAMA. 2018 ;319(8):788-799 Targeting Antibiotic Non-susceptible Gram-negative Organisms (TANGO) Trial – Meropenem+Vaborbactam TANGO I: Complicated

EAHP Academy Seminars 20-21 September 2019 Kaye KS et al. JAMA 2018;319(8):788-799 Targeting Antibiotic Non-susceptible Gram-negative Organisms (TANGO) Trial – Meropenem+Vaborbactam TANGO II: Carbapenem-Resistant Enterobacteriaceae Infections

EAHP Academy Seminars 20-21 September 2019 Wunderink RG et al. Infect Dis Ther 2018;7:439–455 Take Home Message

• Cefiderocol is a novel substance related to the 3rd and 4rth generation cephalosporins ceftazidime and cefepime but has an additional residue that binds to iron. • The unique structure of cefiderocol results in an increased concentration of the antibiotic in the bacterium thus bypassing some but not all resistance mechanisms. • Several combinations of cephalosporins and carbapenems with beta-lactamase inhibitors result in an increased activity against multiresistant gram-negative bacteria. • To this end none of the novel compounds demonstrates to be vastly superior to existing ß-lactam antibiotics but some may be effective against otherwise resistant bugs.

EAHP Academy Seminars 20-21 September 2019 Antibacterial Targets Inhibitors of cell wall assembly

Inhibitors of Lipid A Biosynthesis

EAHP Academy Seminars 20-21 September 2019 UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) Role in bacterial wall formation Effect of lpxC inhibition on e.coli growth

EAHP Academy Seminars 20-21 September 2019 Onishi HR et al. Science 1996;274(5289):980-982 In Vitro Activity of LpxC Inhibitors

EAHP Academy Seminars 20-21 September 2019 Krause KM et al. Antimicrob Agents Chemother doi:10.1128/AAC.00977-19 In Vivo Bactericidal Activity of ACHN-975 Neutropenic Mouse Thigh Model, Multiresistant Pseudomonas aeruginosa

Vehicle control ACHN-975 5mg/kg

ACHN-975 10mg/kg o ACHN-975 30mg/kg

EAHP Academy Seminars 20-21 September 2019 Krause KM et al. Antimicrob Agents Chemother 2019 doi:10.1128/AAC.00977-19 ACHN-975 seems to be an ideal compound but… Effect of ACHN-975 on heart rate and systolic pressure of male Sprague–Dawley rats

EAHP Academy Seminars 20-21 September 2019 Mod. from Cohen F et al. ChemMedChem. 2019;14(16):1560-1572 Take Home Message

• Inhibitors of the UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) have bactericidal activity against gramnegative bacteria. • The most potent candidate is ACHN-975 with nanomolar affinity to LpxC. • Unfortunately ACHN-975 and related compounds have negative effects on the cardiovascular system. • To this end no clinical trials are performed with any LpxC inhibitor.

EAHP Academy Seminars 20-21 September 2019 Antibacterial Targets Inhibitors of protein synthesis

Pleuromutilins

EAHP Academy Seminars 20-21 September 2019 Pleuromutilins

Pleuromutilin Retapamulin Levamulin (Altargo®, topical cream) (XenletaTM, oral, i.v.)

EAHP Academy Seminars 20-21 September 2019 Levamulin Evaluation Against (LEAP 1) Trial Trial design Patients screened: n=586

RandomisedExcluded: n:=43 n=551

Moxifloxacin (iv/o) Levamulin (iv/o): n=276 (MRSA: +Linzolid): n=275

Clinically evaluable: n=245 Clinically evaluable: n=236

Endpoints: 1. clinical and microbiological response; 2. safety, clinical response by baseline

EAHP Academy Seminars 20-21 September 2019 Mod. from File TM S et al. Clin Inf Dis. 2019;XX:1-9 DOI: 10.1093/cid/ciz090 Levamulin Evaluation Against Pneumonia (LEAP 1) Trial Results 1

EAHP Academy Seminars 20-21 September 2019 Mod. from File TM S et al. Clin Inf Dis. 2019;XX:1-9 DOI: 10.1093/cid/ciz090 Levamulin Evaluation Against Pneumona (LEAP 1) Trial Results 2 Early Clinical Response Investigator assessment of clinical response 100% 10,5% 7,6% Non-Responder 15,8% 14,7% 80% Indeterminant Clinical Clinical 60% Responder

90,2% 40% 87,3% 81,7% 84,2% Achieving Response

20% Patients 0% Lefamulin Lefamulin Moxifloxacin EAHP Academy Seminars 20-21 September 2019 Mod. from File TM S et al. Clin Inf Dis. 2019;XX:1-9 DOI: 10.1093/cid/ciz090 Take Home Message

• Pleuromutilins selectively inhibit bacterial translation through binding to the 50s ribosomal subunit. • Tiamulin and valnemulin are two established pleuromutilins in veterinary medicine. • Levamulin is the first candidate for systemic use and exhibits activity against a number of resistant bacteria. • The LEAP trial demonstrates non-inferiority of Levamulin against Moxifloxacin alone or in combination with Linezolid. • To this end resistance patterns caused by the use of pleuromutilins in veterinary medicine cannot be anticipated.

EAHP Academy Seminars 20-21 September 2019 Bacteriophages – Friend of Foe?

Félix d'Hérelle, discoverer of phage therapy

EAHP Academy Seminars 20-21 September 2019 Newsweek, May 24-31 2019 http://gallica.bnf.fr/ark:/12148/btv1b32000224/f64.item Bacteriophage preparation targeting antibiotic-resistant Pseudomonas aeruginosa in chronic otitis Trial design Patients screened: n=44

RandomisedExcluded: n=43: n=24

Bacteriophages (200µL=100,000pfu Placebo (200 µL saline): n=12 BC-BP 01-06): n=12

Clinically evaluable: n=12 Clinically evaluable: n=12

Endpoints: 1. Patient reported and Physician assessed appearance; 2. Bacterial levels of P.a. EAHP Academy Seminars 20-21 September 2019 Mod. from: Wright A et al. Clin. Otolaryngol. 2009, 34, 349–357 Bacteriophage preparation targeting antibiotic-resistant Pseudomonas aeruginosa in chronic otitis

EAHP Academy Seminars 20-21 September 2019 Mod. from: Wright A et al. Clin. Otolaryngol. 2009, 34, 349–357 Bacteriophage therapy of ventilator-associated pneumonia and empyema caused by Pseudomonas aeruginosa Case Report • 77 year old female post thoracotomy after adenocarcinoma of the right lower lobe • On the second day increased white blood cell count and CRP • After two weeks of intravenous antibiotic treatment detection of multiresistant Pseudomonas aeruginosa in BAL • On day 23 AB-PA01 (AmpliPhi Biosciences Corporation) a phage product of four obligately lytic bacteriophages (two Myoviridae and two Podoviridae, each at ~1 × 109 plaque-forming units (PFU)/mL) was administered intravenously and via nebuliser

EAHP Academy Seminars 20-21 September 2019 Maddocs S et al AJRCCM Articles in Press. 2019 10.1164/rccm.201904-0839LE Case Report: Successful Treatment of Pneumonia

EAHP Academy Seminars 20-21 September 2019 Maddocs S et al AJRCCM Articles in Press. 2019 10.1164/rccm.201904-0839LE Take Home Message

• Bacteriophages have been used for more than a century to treat bacterial infections but sound scientific results are scarce. • Case studies and small size clinical trials have demonstrated that bacteriophages seem to be effective against multiresistant bacteria with reasonable safety and tolerability. • Development, production and administration of bacteriophages is dependent of the respective microbial pattern and therefore hard to be upscaled. It is unlikely that bacteriophages will become a household off the shelf therapy any time soon.

EAHP Academy Seminars 20-21 September 2019 Hugstetter Str. 55 D-79106 Freiburg GERMANY +49 761-270-54510 [email protected]