Evaluation of Antibiotics Active against Methicillin-Resistant Staphylococcus aureus Based on Activity in an Established Biofilm

Abstract

We used in vitro and in vivo models of catheter-associated biofilm formation to compare the relative activity of antibiotics effective against methicillin-resistant Staphylococcus aureus (MRSA) in the specific context of an established biofilm. The results demonstrated that, under in vitro conditions, daptomycin and ceftaroline exhibited comparable activity relative to each other and greater activity than vancomycin, telavancin, oritavancin, dalbavancin, or tigecycline. This was true when assessed using established biofilms formed by the USA300 methicillin-resistant strain LAC and the USA200 methicillin-sensitive strain UAMS-1. Oxacillin exhibited greater activity against UAMS-1 than LAC, as would be expected, since LAC is an MRSA strain. However, the activity of oxacillin was less than that of daptomycin and ceftaroline even against UAMS-1. Among the lipoglycopeptides, telavancin exhibited the greatest overall activity. Specifically, telavancin exhibited greater activity than oritavancin or dalbavancin when tested against biofilms formed by LAC and was the only lipoglycopeptide capable of reducing the number of viable bacteria below the limit of detection. With biofilms formed by UAMS-1, telavancin and dalbavancin exhibited comparable activity relative to each other and greater activity than oritavancin. Importantly, ceftaroline was the only antibiotic that exhibited greater activity than vancomycin when tested in vivo in a murine model of catheter-associated biofilm formation. These results emphasize the need to consider antibiotics other than vancomycin, most notably, ceftaroline, for the treatment of biofilm-associated S. aureus infections, including by the matrix-based antibiotic delivery methods often employed for local antibiotic delivery in the treatment of these infections.

Versatility of targeted antibiotic-loaded gold nanoconstructs for the treatment of biofilm-associated bacterial infections

“…This is particularly true when the concentration of vancomycin present following irradiation (3.7 μg/ml) is viewed in the context of the breakpoint minimum inhibitory concentration (MIC) for vancomycin susceptibility (2.0 μg/ml). Moreover, previous studies from our group have demonstrated that concentrations this low have little to no effect on bacterial viability within the context of a biofilm [20]. Whether these relatively low concentrations are a function of a reduced capacity to load vancomycin or a reduced capacity to achieve its PT-mediated release is not clear, but it should be noted that vancomycin is also a relatively large antibiotic (Fig.…”

“…Moreover, the amount of antibiotic released in the absence of laser irradiation was <2 μg/ml, and our previous studies would suggest that this concentration is not effective in the context of an established S. aureus biofilm [20]. This suggests that the killing observed 24 hrs after exposure to the AuNC@Dap/PDA-aMntC formulation in the absence of laser irradiation may be due to some other factor.…”

“…Specifically, we chose to load ceftaroline or vancomycin into AuNC@PDA. Ceftaroline was also chosen because of previous studies demonstrating its relatively high level of activity within established S. aureus biofilms [20]. For studies testing alternative antibiotics, the antibiotic component was changed and the antibody held constant, with all formulations against S. aureus being conjugated to aSpa.…”

“…While these results were limited to in vitro studies, it is important to note that we have not been able to achieve a comparable effect under such conditions using any existing antibiotic alone [20]. Thus, we believe this approach offers tremendous therapeutic promise, particularly in the context of biofilm-associated infections.…”

“…Before addition to the wells, all AuNC formulations were sonicated to disrupt aggregates (Bransonic 2800; Branson). For the assessment of formulations loaded with daptomycin, the BFM was supplemented with 2.5 mM CaCI 2 [20], All plates were covered with a gas-permeable sealing membrane (Diversified Biotech) to prevent evaporation during irradiation. As assessed using a power meter (Newport Power Meter Model 1918-R, Newport Corp., Irvine CA), this membrane was previously shown to reduce the laser power reaching the underlying catheters by ~30% [9].…”