MRSA across roads: new antibiotic options Javier Garau, MD, PhD University of Barcelona 18th Infection and Sepsis Symposium, BUGS, MUGS AND DRUGS, Porto, 27th February 2013 DISCLOSURES I have accepted grants, speaking invitations and conference invitations from Astellas, AstraZeneca, Bayer, GSK, Novartis, Pfizer and Vifor Pharma I have had recent or ongoing consultancy with Astellas, AstraZeneca, Bayer, Durata, GSK, Janssen, Novartis, Pfizer, Theravance and Vifor Pharma Current treatment options for MRSA infections and their limitations • Agents with anti-MRSA activity include: Vancomycin Linezolid Teicoplanin Tigecycline Daptomycin Co-trimoxazole Telavancin Tedizolid Ceftaroline Ceftobiprole Oritavancin Dalbavancin • Limitations of current therapy: – Progressive limitations of vancomycin – Daptomycin not effective in pneumonia – Non-susceptible daptomycin MRSA after glycopeptide exposure – Plasmid-mediated resistance to linezolid – Poor outcomes in left-sided infective endocarditis The Clinical Significance of Vancomycin Minimum Inhibitory Concentration in Staphylococcus aureus Infections: A Systematic Review and Meta-analysis Quality of reporting of meta-analysis profile showing flow of studies included in the meta-analysis. van Hal SJ et al. CID 2012 Vancomycin MIC was significantly associated with treatment failure irrespective of source of infection or MIC methodology Mantel-Haenszel analysis of events denoting S. aureus vancomycin treatment failure (irrespective of definition, source of infection and MIC methodology used) comparing high vancomycin MIC (>1.5 lg/mL) with low MIC (<1.5 lg/mL) infections. Squares indicate point estimates, and the size of the square indicates the weight of each study. Abbreviations: CI, confidence interval; M-H, Mantel-Haenszel; MIC, minimum inhibitory concentration. van Hal SJ et al. CID 2012 The Clinical Significance of VAN MIC in S.aureus Infections: A Systematic Review and Meta-analysis. Conclusion • Patients with MRSA BSI and higher vancomycin MIC values by Etest have a higher likelihood of mortality and treatment failure. • The cause is not well defined; most likely reflects an interaction among pathogen-specific variables, host responses, and suboptimal vancomycin exposure. • Non vancomycin anti-MRSA therapies should be considered for patients with MRSA BSI with high vancomycin MIC, especially for values >2.0 μg/mL by Etest. • There are currently no data to support better survival rates with alternative antibiotics for MRSA BSI. van Hal SJ et al. CID 2012 Differential characteristics of patients with bacteremia caused by MSSA strains with a MIC to vancomycin >1.5 μg/mL compared with <1.5 μg/mL by Etest* *Values are no. (%) except as indicated. MSSA, methicillin-susceptible Staphylococcus aureus; IV, intravenous. †Antistaphylococcal E -lactams refers to parenteral cloxacillin, cefazolin, amoxicillin-clavulanate, piperacillin-tazobactam, or imipenem/meropenem. ‡Including non–E -lactam antibiotics with in vitro activity against MSSA (mostly levofloxacin, moxifloxacin or, clindamycin). Delay since isolation of MSSA in blood cultures. ¶Removal of catheter in the first 48 hours since isolation of MSSA in blood cultures. Aguado JM et al. EID 2011 #Catheter kept at least 7 days since isolation of MSSA in blood cultures. Antibiotic choice may not explain poorer outcomes in patients with S aureus bacteremia and high VAN MIC concentrations. • We assessed 532 patients with SAB from 8 hospitals. • All patients with MRSA bacteremia were treated with VAN, and patients with MSSA bacteremia received either flucloxacillin or VAN. Increasing VAN MIC was associated with increased mortality in VAN-treated patients. • However, even in patients with MSSA bacteremia treated with flucloxacillin, mortality was also higher if the vancomycin Etest MIC of their isolate was >1.5 μg/mL, compared with those with lower MIC isolates (26.8% vs 12.2%; P < .001). • After adjustment in a multivariate model, age, hospital-onset SAB and vancomycin MIC were independently associated with mortality, but methicillin resistance and antibiotic choice were not. Holmes NE et al. JID 2011 In Vivo Efficacy of Tedizolid, Linezolid and Vancomycin • The antibacterial efficacies of tedizolid phosphate (TZD), linezolid and vancomycin regimens simulating human exposures at the infection site against MRSA were compared in an in vivo mouse pneumonia model • Immunocompetent BALB/c mice were orally inoculated with one of three strains of MRSA • Drug regimens used produced epithelial lining fluid exposures comparable to human exposures observed following intravenous regimens of 200 mg Q24 TZD, 600 mg Q12 linezolid and 1g Q12 VAN Tessier PR et al. AAC 2012 Comparative In Vivo Efficacy of Epithelial Lining Fluid Exposures of Tedizolid, Linezolid and Vancomycin for MRSA in a Mouse Pneumonia Model Changes in bacterial density after 24h for tedizolid , LZD , and VAN ELF concentration time course of 20 mg/kg Q24 treated groups (bar level represents average change in log10 CFU tedizolid, 120 mg/kg 454 Q12 LZD and 25 mg/kg of group from initial density, error bars 1 SD). Q12 VAN over 24h in mice. †= Significant different from tedizolid and LZD, p ≤0.016. ‡= Significantly different from LZD, p ≤0.026. The VAN regimen was less protective than either the TZD or linezolid regimens, with overall survival of 47 61.1% versus 94.7% and 89.5%, respectively. Tessier PR et al. AAC 2012 In vitro activity of dalbavancin, oritavancin, telavancin and vancomycin against Gram-positives Zhanel GG et al. Drugs 2010 Chemical structure of ceftaroline Adapted from Zhanel GG et al. Drugs 2009 Comparative in vitro MIC 90s of Ceftaroline and Other Comparators against Gram-Positive Bacteria aCeftaroline MIC breakpoints areas follows: S. aureus < 1 for skin isolates only, S. pneumoniae < 0.25 lg/mL for community-acquired bacterial pneumonia isolates only, Streptococcus pyogenes < 0.015 for skin isolates only, and Streptococcus agalactiae <0 .03 lg/mL for skin isolates only. Saravolatz LD et al. CID 2012 Activity of Ceftaroline and Comparator Antimicrobial Agents Against 3329 Streptococcus pneumoniae Isolates Recovered in the United States During 2008–2010 a As defined by CLSI criteria. b FDA break points were applied when available: S. pneumoniae, susceptible ≤0.25 μg/mL; no resistance category. c “Penicillin parenteral (non-meningitis),” as defined by the CLSI. d “Penicillin (oral penicillin V),” as defined by the CLSI. e FDA break points were applied when available Farrell DJ et al. CID 2012;55(S3):S206–14 Binding affinities of ceftaroline, cefotaxime, and ceftriaxone for pneumococcal PBPs Among 3 PenR S. pneumoniae, ceftaroline had a high affinity for PBP2X, a primary target for cephalosporin PBP binding activity, and high affinities for PBP2B and PBP1B, are also major targets for PBP binding activity of cephalosporins. 15 Kosowska-Shick K et al. AAC 2010 MIC50/MIC90 and MBC50/MIC90 values for all antimicrobials tested for their activities against CA- MRSA,VISA, and hVISA Saravolatz L et al. AAC 2010 In vitro activity of ceftaroline against 623 diverse strains of anaerobic bacteria •Against gram-positive strains, the activity of ceftaroline was similar to that of amoxicillin/clavulanate and 4 to 8 times greater than ceftriaxone. Against gram-negative organisms, ceftaroline showed good activity against β- Lactamase negative strains, Citron DM et al. AAC 2010 Comparative in vitro MIC 90s of Ceftaroline and Other Comparators against Gram-negative Bacteria Ceftaroline breakpoints are as follows: Enterobacteriaceae sensitive < 0.5, and resistant > 2 lg/mL for CABP and skin isolates. Haemophilus influenzae < 0.12 lg/mL for CABP isolates only Saravolatz LD et al. CID 2012 1. f % T > MIC targets of 35, 44 and 51 for CPT are associated with net bacterial stasis and a 1- and 2-log10 CFU reduction from baseline of SP, respectively, based on data from a neutropenic murine infection model. Van Wart SA et al. 2012 ICAAC Ceftaroline PK/PD • An in vitro pharmacodynamic study (hollow fibre model) examining simulated regimens of 600 mg of ceftaroline every 12 h and 600 mg of ceftaroline every 8 h. • For the studied strains with an MIC of 0.5 mg/L, the every 12 h regimen produced a free T>MIC of 83%, whereas the every 8 h regimen produced a free T>MIC of 100%. • At an MIC of 1 mg/L, the Q 8 h regimen produced a free T>MIC of 92%. • In severe infections such as endocarditis, the more aggressive dose of 600 mg every 8 h to ensure an optimal percentage T>MIC is recommended. Vidaillac et al. Int J Antimicrob Agents 2010;. Ho TT et al. JAC 2012 In Vivo Efficacy of Ceftaroline, Compared with Linezolid and Vancomycin against MRSA and VISA in a Rabbit Endocarditis Model Bacterial titers in vegetations after 4 days of treatment Ceftaroline regimen mimicking the human dose of 10 mg/kg q 12h (600 mg q12h) Linezolid regimen mimicking the human dose of 10 mg/kg q12h (600 mg q12h) Vancomycin administered by a constant IV infusion in order to reach a steady-state 20 X MIC in serum Jacqueline C et al. AAC 2007 In Vivo Activity of Ceftaroline, against Vancomycin-S and -R Enterococcus faecalis Strains in a Rabbit Endocarditis Model Bacterial titers in vegetations after 4 days of treatment EF 12704 is susceptible to vancomycin (Vans), and EF NJ1 exhibits a Vanr VanA phenotype. The MICs of ceftaroline, linezolid, and vancomycin for strains EF 12704 and EF NJ1 were 2 and 1 mg/liter, 2 and 1 mg/liter, and 2 and 256 mg/liter. Jacqueline C et al. AAC 2009 Efficacy of ceftaroline in the treatment of experimental MRSA acute osteomyelitis. Rabbit model of acute osteomyelitis. Efficacy assessed following 4 days of treatment by colony counts of infected bone tissues (joint fluid, femoral bone marrow and bone). • Vancomycin was ineffective against the MRSA strain and poorly active against GISA infections in this model. • Ceftaroline and linezolid demonstrated significant activity in bone marrow and bone, and were significantly better than vancomycin treatment. • Ceftaroline was the only drug to exhibit significant activity against MRSA in infected joint fluid. Jacqueline C et al.