Antibiotics And DFIs: What The Evidence Reveals

Anne Spichler, MD, PhD, and David G. Armstrong, DPM, MD, PhD

   The antibacterial activity of ceftaroline is similar to that of other ß-lactams and occurs by binding to penicillin-binding proteins (PBP) and accordingly interfering with cell wall synthesis. Ceftaroline binds to PBP 1–4 and has an especially high affinity for PBP2a (mecA), which is associated with methicillin resistance. This unique affinity for PBP2a distinguishes ceftaroline from other cephalosporins. Ceftaroline is a broad-spectrum cephalosporin with bactericidal activity against Gram-positive bacteria, including MRSA and MRSA strains such as Panton Valentine-leukocidin-producing strains.

   Ceftaroline also has bactericidal activity against strains that are resistant to other classes of antimicrobial agents such as glycopeptides, daptomycin, clindamycin, sulfamethoxazole-trimethoprim (Bactrim, Roche) and linezolid.10 Patients tolerate ceftaroline well and the agent has an adverse effect profile similar to that of other cephalosporins. Furthermore, it has excellent bioavailability via intramuscular administration.

   A randomized study compared ceftaroline with other antibiotics such as vancomycin in adults with complicated skin and skin structure infections.11 However, the study authors excluded diabetic foot ulcers from this study. The results showed that ceftaroline had similar efficacy to the comparator group in treating overall infections including a MRSA subset.

   This antibiotic is approved for the treatment of acute bacterial skin and skin structure infections.10 Perhaps a future study will assess the use of ceftaroline as empiric therapy for diabetic foot infections with MRSA and when there is a noted resistance to vancomycin.

Investigating The Potential Of A Ceftaroline/Avibactam Combination

With the increased incidence of MRSA and extended-spectrum ß-lactamase (ESBL) producing Enterobacteriaceae in diabetic foot infections, there is probably a need for the use of two antimicrobials, one for the usual mixed aerobic (including extended-spectrum ß-lactamase producers) and anaerobic pathogens, and a second agent to ensure MRSA activity.12,13 Ceftaroline has excellent in vitro activity against staphylococci and MRSA, but limited activity against extended-spectrum ß-lactamase producing organisms.

   Avibactam is a non–ß-lactam, ß-lactamase inhibitor, which shows little or no activity against anaerobes. However, it confers activity against resistant aerobic Gram-negative bacteria, including those that produce carbapenemases. These factors make a ceftaroline/avibactam combination potentially well suited for use in diabetic foot infections.

   Accordingly, Goldstein and colleagues evaluated the potential of this antibiotic combination against the full range of culture isolates clinicians encounter in moderate to severe diabetic foot infections.12 Researchers tested 316 aerobic pathogens and 154 anaerobic pathogens recovered from patients with moderate to severe diabetic foot infections. All of the Staphylococcus spp., Enterobacteriaceae, B. fragilis and group species tested positive for ß-lactamase production. The study results showed markedly improved activity against anaerobic Gram-positive cocci, including Finegoldia magna, a common diabetic foot pathogen, clostridia, anaerobic Gram-positive rods, the beta-lactamase producing Prevotella, Porphyromonas species, Bacteroides fragilis and B. caccae.

   While ceftaroline alone has excellent activity against most of the aerobic component of pathogens in moderate to severe diabetic foot infections, this study shows that the addition of avibactam results in a broader spectrum of antibiotic coverage. Ceftaroline/avibactam is a promising agent for monotherapy against the wide spectrum of diabetic foot infection isolates.

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