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. 2016 Sep 23;60(10):5688-94.
doi: 10.1128/AAC.01251-16. Print 2016 Oct.

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

Daniel G Meeker  1 , Karen E Beenken  1 , Weston B Mills  1 , Allister J Loughran  1 , Horace J Spencer  2 , William B Lynn  1 , Mark S Smeltzer  3
Affiliations

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

Daniel G Meeker et al. Antimicrob Agents Chemother. .

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.

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Figures

FIG 1
FIG 1
Relative capacity of UAMS-1 and LAC to form a biofilm in vitro. The relative capacity of each strain to form a biofilm was evaluated using our catheter model after 24 and 72 h of colonization without antibiotic exposure. Results are shown as the number of CFU per catheter, with each box illustrating the maximum and minimum values observed within each experimental group and the horizontal line indicating the mean for that group. *, statistically significant difference (P < 0.05) between the number of viable biofilm-associated bacteria formed by LAC relative to the number of viable biofilm-associated bacteria formed by UAMS-1 at 72 h.
FIG 2
FIG 2
Relative activity of different antibiotics against LAC and UAMS-1 at 24 h in the context of a biofilm in vitro. Activity was evaluated using daptomycin (DAP), vancomycin (VAN), ceftaroline (CPT), oxacillin (OXA), telavancin (TLV), and tigecycline (TGC) at concentrations corresponding to 5×, 10×, and 20× the breakpoint MIC for each antibiotic. Results are shown as the number of CFU per catheter, with each box illustrating the maximum and minimum values observed within each experimental group and the horizontal line indicating the mean for that group. Gray bars, results observed with catheters that were not exposed to any antibiotic; white bars, results observed after exposure of UAMS-1 (top) or LAC (bottom) biofilms to the indicated antibiotics; *, significant reduction in the number of viable bacteria (P ≤ 0.05) relative to that achieved with vancomycin at the equivalent concentration.
FIG 3
FIG 3
Relative activity of different antibiotics against LAC and UAMS-1 at 72 h in the context of a biofilm in vitro. Activity was evaluated using daptomycin (DAP), vancomycin (VAN), ceftaroline (CPT), oxacillin (OXA), telavancin (TLV), and tigecycline (TGC) at concentrations corresponding to 5×, 10×, and 20× the breakpoint MIC for each antibiotic. Results are shown as the number of CFU per catheter, with each box illustrating the maximum and minimum values observed within each experimental group and the horizontal line indicating the mean for that group. Gray bars, results observed with catheters that were not exposed to any antibiotic; white bars, results observed after exposure of UAMS-1 (top) or LAC (bottom) biofilms to the indicated antibiotics. *, significant reduction in the number of viable bacteria (P ≤ 0.05) relative to that achieved with vancomycin at the equivalent concentration; **, significant reduction relative to that achieved with daptomycin at the equivalent concentration.
FIG 4
FIG 4
Evaluation of telavancin activity in vitro. Activity was evaluated by comparison of the activity of daptomycin at a concentration corresponding to 20× the breakpoint MIC (gray bars) to that of telavancin at 40×, 80×, and 160× the breakpoint MIC (white bars). Results are shown as the number of CFU per catheter, with each box illustrating the maximum and minimum values observed within each experimental group and the horizontal line indicating the mean for that group. *, significant reduction in the number of viable bacteria (P ≤ 0.05) achieved with daptomycin at 20× the breakpoint MIC relative to that achieved with telavancin at 160× the breakpoint MIC.
FIG 5
FIG 5
Comparison of the activity of lipoglycopeptide antibiotics in vitro. The activities of telavancin (TLV), oritavancin (ORV), and dalbavancin (DBV) at an equal concentration corresponding to 160× the breakpoint MIC of telavancin (19.2 μg per ml) were compared. The results obtained with catheters that were exposed to antibiotic (white bars) for 72 h relative to those obtained with catheters that were not exposed to antibiotic (gray bars) are shown. Results are shown as the number of CFU per catheter, with each box illustrating the maximum and minimum values observed within each experimental group and the horizontal line indicating the mean for that group. *, significant reduction in the number of viable bacteria (P ≤ 0.05) relative to that achieved with oritavancin; **, significant reduction relative to that achieved with dalbavancin.
FIG 6
FIG 6
Relative activity of different antibiotics assessed in vitro based on the MIC. Activity was evaluated after 72 h of exposure using daptomycin (DAP), ceftaroline (CPT), vancomycin (VAN), and oxacillin (OXA) at concentrations corresponding to 20× (top) and 40× (bottom) the MIC for each test strain, as determined by Etest. Gray bars, results observed with catheters that were not exposed to any antibiotic; white bars, results observed after exposure to the indicated antibiotics. *, significant reduction in the number of viable bacteria (P ≤ 0.05) relative to the number of untreated control bacteria; **, significant reduction relative to that achieved with vancomycin at the equivalent concentration.
FIG 7
FIG 7
Relative activity of different antibiotics assessed in vivo. Catheters colonized with LAC were evaluated after 5 days of exposure to daptomycin (DAP), ceftaroline (CPT), vancomycin (VAN), and telavancin (TLV) at a concentration corresponding to 20× (left) or 40× (right) the breakpoint MIC for each antibiotic. Gray bars, results observed with catheters that were not exposed to any antibiotic; white bars, results observed after exposure to the indicated antibiotics. *, significant reduction in the number of viable bacteria (P ≤ 0.05) relative to the number of untreated control bacteria; **, statistical significance by comparison to the results obtained with vancomycin.
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