Portfolio de nuevos antibióticos para grampositivos

Dr. Jose Luis del Pozo Área de Enfermedades Infecciosas y Microbiología Clínica

Clínica Universidad de Navarra. Pamplona Madrid, Diciembre de 2017

Antibiotic resistance is ancient D’Costa et al., Nature 2011

DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to β-lactam, tetracycline and glycopeptide antibiotics

Antimicrobial Resistance Marston et al., JAMA 2016

Antimicrobial Resistance Marston et al., JAMA 2016

Risk factors associated with long-term prognosis of patients with Staphylococcus aureus bacteremia.

Hanses et al., Infection. 2010

Supervivencia 60%

Supervivencia < 40%

Risk factors associated with long-term prognosis of patients with Staphylococcus aureus bacteremia.

Hanses et al., Infection. 2010

25%

Antibiotic choice may not explain poorer outcomes in patients with S. aureus bacteremia and high vancomycin MIC

Holmes et al., J Infect Dis 2011

MSSA MRSA

Methicillin-Resistant Staphylococcus aureus Therapy: Past, Present, and Future

Rodvold et al., Clin Infect Dis 2014

Novedades para cocos grampositivos resistentes

Ceftarolina fosamil Zinforo (600 mg/12h IV) •  SARM, VISA, VRSA •  Neumococo peniR,

CF·R •  E. faecalis vanco R •  Enterobacterias (no

BLEES, no AmpC, no CBP)

•  NAC, IPPBc

Ceftobiprole medocaril Zevtera (500 mg/8h IV) •  SARM, E. faecalis

ampiR, Enterobacterias (no BLEES, no AmpC,no CBP)

•  NAC, NN, IPPBc

Fosfato de Tedizolid Sivextro (200 mg/24h x 6 d) •  SARM, VISA •  IPPBc

Dalbavancina Xydalba (1g d0, 0,5g d8)

•  SARM, VISA •  IPPBc

Telavancina Vivatib (10 mg/Kg/d)

•  SARM, VISA •  Warnings FDA:

Nefrotoxicidad, QT, C difficile

•  NN, NAV

Oritavancina Orbactiv (1500 mg/d)

•  SARM, VISA, VRSA •  IPPBc

Pubmed 1 de Diciembre de 2017 8496

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Vancomicina Linezolid Daptomicina Teicoplanina Ceftarolina Dalbavancina Ceftobiprole Tedizolid

Novedades para cocos grampositivos resistentes

Fosfato de Tedizolid Sivextro (200 mg/24h x 6 d) •  SARM, VISA •  IPPBc

In Vitro Activity of TR-700, the Antibacterial Moiety of the Prodrug TR-701, against Linezolid-Resistant Strains

Shaw et al., Antimicrob Agents and Chem 2008

Structure-Activity Relationships of Diverse Oxazolidinones for Linezolid-Resistant S. aureus Strains Possessing the cfr

Methyltransferase Gene or Ribosomal Mutations Locke et al., Antimicrob Agents and Chem 2010

Mutantes ribosómicos

Structure-Activity Relationships of Diverse Oxazolidinones for Linezolid-Resistant S. aureus Strains Possessing the cfr

Methyltransferase Gene or Ribosomal Mutations Locke et al., Antimicrob Agents and Chem 2010

Adquisición de cfr

Analysis of the Phase 3 ESTABLISH Trials of Tedizolid versus Linezolid in Acute Bacterial SSTI

Shorr et al., Antimicrob Agents and Chem 2015

High Frequency of Linezolid-Associated Thrombocytopenia and Anemia among Patients with End-Stage Renal Disease

Wu et al., Clin Infect Dis 2006

Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment

Flanagan et al., Antimicrob agents and Chem 2014

Renal impairment Hepatic impairment

In Vitro, In Vivo, and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase

Interactions Flanagan et al., Antimicrob agents and Chem 2013

Potencial posicionamiento de Tedizolid

1.  IPPB por SARM en pacientes …. –  …con R a linezolid por adquisición del gen cfr –  …con alteraciones hematológicas de base –  …con insuficiencia renal –  …con cirrosis hepática –  …tratados con ISRS

2.  Actividad frente a micobacterias

Novedades para cocos grampositivos resistentes

Dalbavancina Xydalba (1g d0, 0,5g d8)

•  SARM, VISA •  IPPBc

Dalbavancin: A Novel Lipoglycopeptide Antibiotic with Extended Activity Against Gram-Positive Infections

Smith et al., Infect Dis Ther 2015

Aumento actividad frente a GP

Aumento T1/2 Aumento unión a lípido II

Worldwide assessment of dalbavancin activity and spectrum against over 6000 clinical isolates.

Streit et al., Diag Microbiol and Infect Dis 2004

In vivo pharmacodynamic activity of the glycopeptide dalbavancin.

Andes et al., Antimicrob Agents Chemother. 2007

PK: •  Dosis: 1000 mg seguido de 500 mg a

la semana (1500 mg una dosis) •  Cmax: 280 mg/L •  Vd: 0.52 L/Kg. Concentraciones en

riñón, hígado, hueso, piel, músculo 14 días de administrar 1000 mg en dosis única

•  Fijación proteica: 93% •  Eliminación urinaria: 42% (No ajuste

si ClCr>30 o HD) •  No necesidad de ajuste en IH

PK/PD: fAUC24h/CMI >245

Extended-duration dosing and distribution of dalbavancin into bone and articular tissue.

Dunne et al., Antimicrob Agents Chemother. 2015

Extended-duration dosing and distribution of dalbavancin into bone and articular tissue.

Dunne et al., Antimicrob Agents Chemother. 2015

Once-weekly dalbavancin versus daily conventional therapy for skin infection

Boucher et al., N Eng J Med 2014

Safety of Dalbavancin in the Treatment of SSSI: A Pooled Analysis of Randomized, Comparative Studies

Dunne et al., Safe Drugs 2016

Efficacy and safety of weekly dalbavancin therapy for catheter-related BSI by Gram-positive pathogens.

Raad et al., Clin Infect Dis. 2005

Potencial posicionamiento de Dalbavancina

1.  IPPBc por SARM –  En aquellas situaciones clínicas en las que se plantee un

tratamiento parenteral prolongado –  En aquellas situaciones en las que, tras un período de

hospitalización, se contemple el manejo extrahospitalario de la infección

2.  Infecciones osteoarticulares (prótesis?) 3.  BRC (tratamiento de consolidación) 4.  Profilaxis de colangitis enterocócica recurrente, ITU enterocócica

recurrente, celulitis recurrente

Novedades para cocos grampositivos resistentes

Ceftarolina fosamil Zinforo (600 mg/12h IV) •  SARM, VISA, VRSA •  Neumococo peniR,

CF·R •  E. faecalis vanco R •  Enterobacterias (no

BLEES, no AmpC, no CBP)

•  NAC, IPPBc

Ceftaroline: a novel broad-spectrum cephalosporin with activity against MRSA

Zhanel et al., Drugs 2009

Antimicrobial activity and spectrum of PPI-0903M (T-91825) tested against a worldwide collection of clinical strains.

Sader HS et al.Antimicrob Agents Chemother 2005

Ceftaroline Fosamil: A Brief Clinical Review Shirley et al., Infect Dis Ther 2013

Binding of ceftaroline to penicillin-binding proteins of S. aureus and S. pneumoniae.

Moisan et al., J Antimicrob and Chem 2010

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Cloxacilina Ceftriaxona Ceftarolina

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PBP2a PBP2 PBP3

Antimicrobial Activity of Ceftaroline Tested against Drug-Resistant Subsets of S. pneumoniae from U.S.

Flamm et al., Antimicrob Agents Chem 2014

Ceftaroline: a novel broad-spectrum cephalosporin with activity against meticillin-resistant S aureus.

Zhanel et al., Drugs 2009

PK: •  Dosis: 600 mg/12h (600mg/8h) •  Cmax: 19.0 - 21.0 µg/ •  Vd: 0.37 L/kg (28.3 L), baja unión a proteínas (<20%) •  Vida media: 2.6 horas. •  Eliminación: renal (49.6%) •  Monte Carlo:

–  ClCr 30-50 mL/min: No ajuste –  ClCr 15-30 mL/min: 400 mg/12h –  ClCr < 30 mL/min: 300 mg/12h –  HD: 200 mg/12h post HD

PK/PD: fT/CMI (50-60%)

Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy

and safety of ceftaroline fosamil versus ceftriaxone in patients with CAP

File et al., Clin Infect Dis., 2010

Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient

data meta-analysis of randomized controlled trials Taboada el al., J Antimicrob Chem 2016

Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient

data meta-analysis of randomized controlled trials Taboada el al., J Antimicrob Chem 2016

Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient

data meta-analysis of randomized controlled trials Taboada el al., J Antimicrob Chem 2016

Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and

efficacy of ceftaroline vs vancomycin/aztreonam in cSSTI Corey et al., Clin Infect Dis., 2010

Ceftaroline for the treatment of MRSA bacteremia Pinkney et al., Am J Health-Syst Pharm. 2017

Clinical success 66%

Efficacy of ceftaroline versus vancomycin in an experimental foreign-body and systemic infection model caused by biofilm-producing methicillin-resistant S.epidermidis Domínguez-Herrera et al., Int J antimicrob Agents 2016

Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible

Vancomycin-Intermediate S. aureus in a PK/PD Model Werth et al., Antimicrob Agents Chem 2013

Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible

Vancomycin-Intermediate S. aureus in a PK/PD Model Werth et al., Antimicrob Agents Chem 2013

Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible

Vancomycin-Intermediate S. aureus in a PK/PD Model Werth et al., Antimicrob Agents Chem 2013

Potencial posicionamiento de Ceftarolina

1.  IPPB por SARM 2.  NAC grave por S. pneumoniae. NN por S. aureus. NAVM:

Ceftarolina + Meropenem 3.  BRC o EI por SARM (combinada con daptomicina) 4.  Cualquier infección por SARM donde utilizaríamos un

betalactámico 5.  Infecciones asociadas a biofilms? 6.  Más activo que cloxacilina frente a SASM con MIC elevada a

Vancomicina?

Gracias!