Abstract
Ceftaroline (CPT) is a novel cephalosporin with in vitro activity against Staphylococcus aureus. Ceftaroline exhibits a level of binding affinity for PBPs in S. aureus including PBP2a of methicillin-resistant S. aureus (MRSA). The aims of this study were to investigate the morphological, physiological and molecular responses of MRSA clinical strains and MRSA biofilms to sub-MICs (1/4 and 1/16 MIC) of ceftaroline by using transmission, scanning and confocal microscopy. We have also used quantitative Real-Time PCR to study the effect of sub-MICs of ceftaroline on the expression of the staphylococcal icaA, agrA, sarA and sasF genes in MRSA biofilms. In one set of experiments, ceftaroline was able to inhibit biofilm formation in all strains tested at MIC, however, a strain dependent behavior in presence of sub-MICs of ceftaroline was shown. In a second set of experiments, destruction of preformed biofilms by addition of ceftaroline was evaluated. Ceftaroline was able to inhibit biofilm formation at MIC in all strains tested but not at the sub-MICs. Destruction of preformed biofilms was strain dependent because the biofilm formed by a matrix-producing strain was resistant to a challenge with ceftaroline at MIC, whereas in other strains the biofilm was sensitive. At sub-MICs, the impact of ceftaroline on expression of virulence genes was strain-dependent at 1/4 MIC and no correlation between ceftaroline-enhanced biofilm formation and gene regulation was established at 1/16 MIC. Our findings suggest that sub-MICs of ceftaroline enhance bacterial attachment and biofilm formation by some, but not all, MRSA strains and, therefore, stress the importance of maintaining effective bactericidal concentrations of ceftaroline to fight biofilm-MRSA related infections.
Highlights
Infections caused by methicillin-resistant strains of S. aureus (MRSA) range from those of the skin and surgical sites, infections relating to catheters and prosthetic implants, to bacteremia, endocarditis and pneumonia [1]
Ceftaroline provides an important new treatment option that may help overcome some of the current challenges we face when managing patients with MRSA infections
Numerous studies have shown that subinhibitory concentrations of some antibiotics can modulate bacterial biofilm formation in vitro
Summary
Infections caused by methicillin-resistant strains of S. aureus (MRSA) range from those of the skin and surgical sites, infections relating to catheters and prosthetic implants, to bacteremia, endocarditis and pneumonia [1]. In addition to chronic infections, S. aureus can cause acute diseases, many of which are mediated by the ability of this pathogen to produce surface structures that facilitate tissue colonization, and/or extracellular toxins. Production of these factors is regulated by a quorum-sensing mechanism, predominantly under the control of the accessory gene regulator (agr) operon where the transcription factor AgrA controls the expression of all the virulence factors under the control of the agr system [9, 10]. The sasF gene, which encodes a putative surface anchored protein (SasF) with significant homology to the biofilm-associated protein SasG and the Staphylococcal accessory regulator (sarA), one of the central elements related to the regulation of virulence factors, could play important roles in MRSA biofilm formation [11, 12]
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