Abstract
Staphylococcus aureus biofilm plays a major role in implant-associated infections. Here, the susceptibility of biofilm S. aureus to daptomycin, fosfomycin, vancomycin, trimethoprim/sulfamethoxazole, linezolid, and rifampicin was investigated by isothermal microcalorimetry (IMC). Moreover, the persister status of cells isolated from S. aureus biofilm after treatment with vancomycin was also analyzed. S. aureus biofilm was tolerant to all the antibiotics tested [minimum biofilm bactericidal concentration (MBBC) > 256 μg/ml], except to daptomycin [MBBC and minimum biofilm eradicating concentration (MBEC) = 32 μg/ml] and rifampin (MBBC and MBEC = 128 μg/ml). After the treatment of MRSA biofilm with 1024 μg/ml vancomycin, ∼5% cells survived, although metabolically inactive (persisters). Interestingly, IMC revealed that persister bacteria reverted to a normal-growing phenotype when inoculated into fresh medium without antibiotics. A staggered treatment of MRSA biofilm with vancomycin to kill all the metabolically active cells and daptomycin to kill persister cells eradicated the whole bacterial population. These results support the use in the clinical practice of a therapeutic regimen based on the use of two antibiotics to kill persister cells and eradicate MRSA biofilms. IMC represents a suitable technique to characterize in real-time the reversion from persister to metabolically-active cells.
Highlights
Staphylococcus aureus is a pathogenic organism responsible for a wide variety of bacterial infections affecting different anatomic districts, including bloodstream, respiratory tract, skin, soft tissues, and bone (Kuroda et al, 2001; DeLeo and Chambers, 2009; Tong et al, 2015)
The aims of this study are: (i) to investigate the in vitro anti-biofilm activity of selected antibiotics commonly used in the clinical practice for the management of implant-associated infections due to methicillin- resistant and methicillin-susceptible S. aureus by conventional tests and isothermal microcalorimetry (IMC); (ii) to evaluate the presence of persister cells in biofilm grown in vitro after the exposure to high bactericidal concentrations of vancomycin; (iii) to characterize the persisters metabolic activity and their susceptibility to bactericidal antibiotic agents, such as daptomycin
No differences in Methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) susceptibility profiles were observed, except when bacteria were challenged with trimethoprim/sulfamethoxazole and rifampicin
Summary
Staphylococcus aureus is a pathogenic organism responsible for a wide variety of bacterial infections affecting different anatomic districts, including bloodstream, respiratory tract, skin, soft tissues, and bone (Kuroda et al, 2001; DeLeo and Chambers, 2009; Tong et al, 2015). Biofilms are characterized by cells with a slow- and non-growing phenotype, which are able to survive in the presence of high concentrations of bactericidal antibiotics (Lewis, 2005), contributing to infection relapses. These so-called ‘persister cells’ represent a small percentage of a microbial population, which are genetically susceptible but phenotypically resistant to antimicrobials thanks to their non-growing quiescent state (Fisher et al, 2017; Grassi et al, 2017). Persistence is, markedly distinct from resistance, which is an inherited ability acquired by the total microbial population and it implies the capacity of bacteria to grow and replicate in the presence of high concentrations of antimicrobial with no dependency on the treatment duration (Scholar and Pratt, 2000; Brauner et al, 2016)
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