Abstract
With the antibiotic development pipeline running dry, many fear that we might soon run out of treatment options. High-density infections are particularly difficult to treat due to their adaptive multidrug-resistance and currently there are no therapies that adequately address this important issue. Here, a large-scale in vivo study was performed to enhance the activity of antibiotics to treat high-density infections caused by multidrug-resistant Gram-positive and Gram-negative bacteria. It was shown that synthetic peptides can be used in conjunction with the antibiotics ciprofloxacin, meropenem, erythromycin, gentamicin, and vancomycin to improve the treatment outcome of murine cutaneous abscesses caused by clinical hard-to-treat pathogens including all ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter cloacae) pathogens and Escherichia coli. Promisingly, combination treatment often showed synergistic effects that significantly reduced abscess sizes and/or improved clearance of bacterial isolates from the infection site, regardless of the antibiotic mode of action. In vitro data suggest that the mechanisms of peptide action in vivo include enhancement of antibiotic penetration and potential disruption of the stringent stress response.
Highlights
ESKAPE pathogens (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, E. cloacae) are recognized to be responsible for the majority of difficult-to-treat community-acquired, healthcare-associated, and nosocomial infections [1]
Less attention has been placed on adaptively multidrug-resistant high density bacterial infections for which antibiotics are highly used but no effective therapies currently exist
We show how to enhance the activity of antibiotics to treat multidrug-resistant Gram-positive and Gram-negative bacteria, using peptides that target the bacterial stress response, persister-based resistance and the outer membrane permeability barrier
Summary
ESKAPE pathogens (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, E. cloacae) are recognized to be responsible for the majority of difficult-to-treat community-acquired, healthcare-associated, and nosocomial infections [1]. Less discussed but of even greater concern are infections associated with high bacterial densities (>107 CFU/ml bacteria) especially biofilm and/or abscess infections. High bacterial densities lead to elevated MICs to multiple antibiotics [3] and are extremely difficult to treat with antibiotics [4]. In this context, skin and soft tissue infections (SSTIs) are an emerging problem, a significant burden in health care facilities, and responsible for increased antibiotic administration [5]. It remains a major challenge to translate in vitro findings into in vivo efficacy and compounds that show excellent in vitro activity (e.g., low MIC in defined medium), often work poorly when tested under in vivo conditions
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