Post on 05-Oct-2020
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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
mg/ml
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!