Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37

Abstract

Recent studies have demonstrated that anti-staphylococcal beta-lactam antibiotics, like nafcillin, render methicillin-resistant Staphylococcus aureus (MRSA) more susceptible to killing by innate host defense peptides (HDPs), such as cathelicidin LL-37. We compared the effects of growth in 1/4 minimum inhibitory concentration (MIC) of nafcillin or vancomycin on LL-37 killing of 92 methicillin-susceptible S. aureus (MSSA) isolates. For three randomly selected strains among these, we examined the effects of nafcillin, vancomycin, daptomycin, or linezolid on LL-37 killing and autolysis. Growth in the presence of sub-inhibitory nafcillin significantly enhanced LL-37 killing of MSSA compared to vancomycin and antibiotic-free controls. Nafcillin also reduced MSSA production of the golden staphylococcal pigment staphyloxanthin in 39% of pigmented strains vs. 14% for vancomycin. Among antibiotics tested, only nafcillin resulted in significantly increased MSSA autolysis. These studies point to additional mechanisms of anti-staphylococcal activity of nafcillin beyond direct bactericidal activity, properties that vancomycin and other antibiotic classes do not exhibit. The ability of nafcillin to enhance sensitivity to innate host defense peptides may contribute to its superior effectiveness against MSSA as suggested by studies comparing clinical outcomes to vancomycin treatment.

Antibiotics and Innate Immunity: A Cooperative Effort Towards the Successful Treatment of Infections

“…This complexity may be one unrecognized pharmacodynamic faculty helping to explain the differences in clinical efficacy of different antibiotic classes irrespective of MIC in standard AST testing. For example, vancomycin is a far inferior agent to beta-lactams clinically against S. aureus , despite showing potent activity in vitro [ 25 , 26 ]. These effects may unfortunately contribute to the poorer outcomes of patient who are denied beta-lactam drugs due to penicillin “allergies” listed in their medical records [ 27 ].…”

Broad-spectrum suppression of bacterial pneumonia by aminoglycoside-propagated Acinetobacter baumannii

“…This reduced pathogenesis is dependent upon interactions with the antibacterial host response in the lung. This finding bolsters the concept that antibiotics can sensitize resistant organisms to the host immune response, which has been demonstrated for host-derived antimicrobial peptides [18,19]. Based upon these findings, it is likely that current laboratory-based testing underestimates the in vivo efficacy of existing antibiotics to combat multidrug-resistant pathogens.…”

“…In contrast, antibiotics can cooperate with innate immune effectors to enhance bacterial killing. Exposure to cell wall-active antibiotics enhances MRSA killing by the host-derived antimicrobial peptide, LL-37, and LL-37 killing of Salmonella enterica is enhanced upon exposure to multiple classes of antibiotics [18,19]. Further, A. baumannii has been found to alter…”

The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent

“…While combinations with antibiotics comprise a great quantity of the research, combinations with other antimicrobial agents are also described in this review. Nafcillin MSSA CIs [191] Enterococcus faecium Ceftaroline DAP-susceptible parent strain, R6370, 8019 [192] Ampicillin DAP-susceptible parent strain, 8019; AMPand VAN-resistant isolate [192,193] Ertapenem DAP-susceptible parent strain, R6370, 8019 [192] Oritavancin VAN-resistant CI [194] Oritavancin + Ampicillin…”

“…Furthermore, many studies have proposed that the ability of an antimicrobial agent to synergize with LL-37 depends on whether it is a bactericidal or a bacteriostatic substance. It has been suggested that synergism results when bactericidal agents are paired together, or when bacteriostatic agents are paired; the combination of bacteriostatic and bactericidal substances will lead to an antagonistic interaction [177,191]. Leszczyńska et al also suggest that the synergistic effects between LL-37 and the bactericidal substance are enhanced if the antibiotic targets the bacterial wall structure.…”