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Finegoldia Magna Diane M. Citron ECCMID 2013 R.M. Alden Research Lab In Vitro Activity of Ceftaroline (CPT) and Ceftaroline-Avibactam (CPA) Against 6133 Bristol Parkway, Ste 175 P1624 Culver City, CA 90230 Tel: 310.641.8340 Aerobic and Anaerobic Bacteria Recovered From Diabetic Foot Infections (DFI) Fax: 310.641.8840 www.rmaldenresearch.com Diane M. Citron and Ellie J.C. Goldstein R.M. Alden Research Lab, Culver City, California, USA Abstract Introduction and Purpose Results Conclusion Objectives: Diabetes mellitus (DM) affects ● The American Diabetes Association estimates Table 1. In Vitro Activity (µg/mL) of Ceftaroline, Ceftaroline-Avibactam, Table 2. In Vitro Activity (µg/mL) of Ceftaroline, Ceftaroline-Avibactam, ● Ceftaroline-avibactam showed substantially ● While ceftaroline alone has excellent in vitro more than 26 million Americans and an and Comparator Antimicrobial Agents Against Anaerobic Isolates and Comparator Antimicrobial Agents Against Aerobic Gram-Positive activity against most of the aerobic component that in the United States there are 25.8 million Recovered From Infected Diabetic Foot Wounds Isolates Recovered From Infected Diabetic Foot Wounds increased activity compared with ceftaroline additional 79 million are prediabetic. DFI are diabetics and that ~25% of diabetic patients Organism (no.) Organism (no.) alone against the β-lactamase-producing of pathogens found in moderate to severe Antimicrobial Agenta Range MIC MIC Antimicrobial Agent Range MIC MIC 50 90 50 90 DFIs, with the exception of P. aeruginosa, the most common infectious complication of develop foot ulcerations during their lifetime, Finegoldia magna (20) Staphylococcus aureus (51) Prevotella and Porphyromonas species, with over half of those ulcerations becoming Ceftaroline ≤0.015-0.5 0.25 0.5 Ceftaroline 0.06-025 0.125 0.25 the addition of avibactam results in a DM, and moderate to severe wounds are Ceftaroline-avibactam 0.06-0.25 0.125 0.25 and against Bacteroides fragilis and typically polymicrobial with aerobic (MRSA of infected Ceftaroline-avibactam ≤0.015-0.5 0.06 0.125 Ceftriaxone 1-4 2 4 Bacteroides caccae. While minimum inhibitory broader spectrum of activity that includes Ceftriaxone 0.06-8 8 8 Clindamycin 0.125-4 0.5 4 the β-lactamase-producing Prevotella, increasing concern) and anaerobic ● Staphylococcus aureus is considered the main Clindamycin ≤0.03-64 0.25 2 Ertapenem 0.06-0.5 0.125 0.5 concentrations (MICs) for other B. fragilis group Levofloxacin 0.06-1 0.125 0.25 Ertapenem ≤0.015-1 0.06 0.25 Porphyromonas, and B. fragilis, making organisms. While CPT has excellent activity causative pathogen in early, uncomplicated Piperacillin-tazobactam 0.06-2 1 2 members were reduced, they were mostly in the Levofloxacin 0.25->32 16 >32 ceftaroline a promising agent for monotherapy against most gram-positives including MRSA diabetic foot infections (DFIs). In moderate to Methicillin-resistant S. aureus (29) 4- to 16-µg/mL range (Table 1) Piperacillin-tazobactam ≤0.03-2 0.125 0.25 Ceftaroline 0.25-1 0.5 0.5 against the wide spectrum of DFI isolates. severe infections, polymicrobial infections with Metronidazole 0.06-0.25 0.125 0.25 Ceftaroline-avibactam 0.25-1 0.5 0.5 and most enteric organisms, its activity Ceftriaxone 8->32 32 >32 ● Ceftaroline alone was active (MIC ≤2 µg/mL) b against β-lactamase producing anaerobes aerobic and anaerobic organisms are commonly Anaerobic, gram-positive cocci, other (25) Clindamycin 0.25->64 1 >64 against β-lactamase-producing strains of encountered, including those with methicillin- Ceftaroline ≤0.015-0.5 0.03 0.25 Ertapenem 0.5->32 2 16 and ESBLs is poor. CPA has shown enhanced Ceftaroline-avibactam ≤0.015-0.5 ≤0.015 0.5 Levofloxacin 0.125->32 8 >32 Clostridium Piperacillin-tazobactam 4->64 16 64 sensitive (MSSA) and -resistant S. aureus Ceftriaxone 0.125-16 0.25 0.5 Staphylococcus species, other (20)a activity against such strains. 1-3 ● None of the comparator antimicrobials were (MRSA) Clindamycin ≤0.03->64 0.5 64 Ceftaroline ≤0.015-1 0.125 0.5 Ertapenem ≤0.015-1 0.06 0.5 Ceftaroline-avibactam ≤0.015-1 0.125 0.25 active against the entire spectrum of organisms Methods: MICs for 154 anaerobic and 316 Ceftriaxone 1->32 4 >32 ● Ceftaroline fosamil, the prodrug of ceftaroline, is Levofloxacin 0.5->32 4 >32 as single agents (Table 1) Clindamycin 0.06->64 0.125 0.5 References aerobic pathogens recovered from patients the first cephalosporin approved by the US Food Piperacillin-tazobactam ≤0.03-1 ≤0.03 0.5 Ertapenem 0.06->32 0.25 2 ● Ceftaroline and ceftaroline-avibactam showed with moderate to severe DFI during 2001 to and Drug Administration (FDA) for the treatment Metronidazole 0.125-2 0.5 2 Levofloxacin 0.06-16 0.25 16 1. Citron, D. M., E. J. Goldstein, C. V. Merriam, B. A. Non-sporeforming, gram-positive rods (10)c Piperacillin-tazobactam 0.06-64 1 8 excellent activity against anaerobic gram- Staphylococcus epidermidis (21) Lipsky, and M. A. Abramson. 2007. Bacteriology 2012, were tested and compared with MICs of acute bacterial skin and skin structure Ceftaroline ≤0.015-0.25 ≤0.015 0.125 Ceftaroline 0.03-0.5 0.25 0.25 positive species, including Finegoldia magna, a of moderate-to-severe diabetic foot infections and in obtained for ceftriaxone (CRO), clindamycin infections (including those caused by MRSA). Ceftaroline-avibactam ≤0.015-0.25 ≤0.015 0.125 Ceftaroline-avibactam 0.03-0.5 0.25 0.25 frequent diabetic foot pathogen (Table 1) vitro activity of antimicrobial agents. J Clin Microbiol. (CLI), ertapenem (ETP), levofloxacin (LEV), In addition, ceftaroline fosamil is also now Ceftriaxone ≤0.015-0.5 0.25 0.5 Ceftriaxone 0.5->32 16 32 Clindamycin ≤0.03->64 0.06 0.5 Clindamycin 0.125->64 0.25 >64 45(9):2819-2828. approved by the European Medicines Agency Ertapenem 0.06->32 2 >32 ● Against aerobic gram-positive strains, and piperacillin-tazobactam (PTZ). MIC Ertapenem 0.06-1 0.125 0.5 2. Levofloxacin 0.125->32 2 >32 ceftaroline demonstrated excellent activity that Castanheira, M., H. S. Sader, D. J. Farrell, R. E. testing of aerobes was done by broth for the treatment of complicated skin and soft- Levofloxacin 0.125-4 1 4 Piperacillin-tazobactam 0.125-32 2 4 Mendes, and R. N. Jones. 2012. Activity of ceftaroline- Piperacillin-tazobactam ≤0.03-4 0.25 1 Streptococcus agalactiae (20) was not enhanced by the addition of avibactam tissue infections Ceftaroline ≤0.015-0.03 ≤0.015 ≤0.015 avibactam tested against Gram-negative organism microdilution and by agar dilution for Metronidazole 0.25->32 32 >32 Ceftaroline-avibactam ≤0.015 ≤0.015 ≤0.015 (Table 2) populations, including strains expressing one or more d anaerobes, according to CLSI M7-A8 and ● Ceftaroline demonstrates excellent in vitro Clostridium species (17) Ceftriaxone 0.03-1 0.06 0.06 β-lactamases and methicillin-resistant Staphylococcus Ceftaroline ≤0.015-2 0.25 2 Clindamycin 0.06->64 0.06 >64 ● Among the enteric gram-negative rods, M11-A8 standards. activity against staphylococci and most enteric aureus carrying various staphylococcal cassette Ceftaroline-avibactam ≤0.015-2 0.06 1 Ertapenem ≤0.015-0.03 ≤0.015 0.03 organisms, however, its activity against Levofloxacin 0.25-1 0.5 1 ceftaroline alone showed excellent activity chromosome mec types. Antimicrob. Agents Chemother. Ceftriaxone 0.015-32 1 32 Piperacillin-tazobactam 0.125-0.25 0.125 0.25 Results: CPT and CPA MIC90 for all β-lactamase-producing anaerobic organisms is Clindamycin ≤0.03-64 0.5 32 Streptococcus anginosus (10) with an MIC90 of 0.5 µg/mL. The addition of 56(9):4779-4785. Staphylococcus species including methicillin- 3,4 Ertapenem ≤0.015-4 0.03 1 Ceftaroline ≤0.015-0.03 ≤0.015 ≤0.015 avibactam to ceftaroline reduced the MICs for poor Ceftaroline-avibactam ≤0.015 ≤0.015 ≤0.015 3. Lipsky, B. A., A. R. Berendt, P. B. Cornia, J. C. Pile, Levofloxacin 0.125-32 0.5 16 resistant isolates was 0.5 µg/mL, and for Ceftriaxone 0.06-0.25 0.125 0.25 most strains by 2- to 8-fold, and yielded an E. J. Peters, D. G. Armstrong, H. G. Deery, ● Avibactam (NXL-104) is a non-β-lactam Piperacillin-tazobactam ≤0.015-8 0.125 8 Clindamycin 0.06->64 0.06 >64 J. M. Embil, W. S. Joseph, A. W. Karchmer, E. faecalis and other enterococci was Metronidazole 0.06-4 0.25 2 Ertapenem 0.03-0.25 0.06 0.125 MIC90 of 0.125 µg/mL (Table 3). β-lactamase inhibitor, which alone shows little M. S. Pinzur, E. Senneville, and Infectious Diseases Bacteroides fragilis (19) Levofloxacin 0.125-0.5 0.5 0.5 1 µg/mL. The MIC90 for all comparator agents or no activity. In conjunction with ceftaroline, Piperacillin-tazobactam ≤0.03-0.125 0.06 0.125 Society of America. 2012. Executive summary: 2012. Ceftaroline 2->32 8 >32 Streptococcus dysgalactiae (10) Infectious Diseases Society of America clinical practice for staphylococci were >32 (CRO), >64 (CLI), AVI confers activity against many resistant Ceftaroline-avibactam 0.125-2 0.5 2 Ceftaroline ≤0.015 ≤0.015 ≤0.015 Table 3. In Vitro Activity (µg/mL) of Ceftaroline, Ceftaroline-Avibactam, and Comparator Antimicrobial Agents Against Aerobic Gram-Negative guideline for the diagnosis and treatment of diabetic foot 8 (ETP), 16 (LEV) and 32 (PTZ) µg/mL. anaerobic and aerobic gram-negative bacteria, Ceftriaxone 4->32 32 >32 Ceftaroline-avibactam ≤0.015 ≤0.015 ≤0.015 Ceftriaxone ≤0.015-0.03 0.03 0.03 Isolates Recovered From Infected Diabetic Foot Wounds Clindamycin 0.125->64 0.5 >64 infections.
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