Antibiotics and Staphylococcus aureus—more than meets the MIC

Abstract

The discovery of penicillin in 1928 and its subsequent introduction into clinical practice in 1941, heralded a new era in the treatment of serious bacterial infections, including those caused by Staphylococcus aureus . This organism causes a wide range of infections in humans, with bloodstream infection and endocarditis being the most serious and potentially devastating. However, despite the discovery of antibiotics, S. aureus continues to cause a significant burden of illness around the world, with a high mortality rate for invasive disease [1]. One of the reasons for this is the ability of the organism to continually evolve and adapt to new environments, including antibiotic exposures, resulting in the ongoing accumulation of antibiotic resistance [2]. Remarkably, penicillin-resistant S. aureus was detected within 1 year of the clinical use of penicillin, and the progressive acquisition of antibiotic resistance in S. aureus since that time, particularly methicillin-resistant S. aureus (MRSA), has severely impacted the available antibiotic armamentarium. As an example of how serious this problem is, over the past 10 years, there have been more deaths from invasive MRSA infection than human immunodeficiency virus infection in the USA [3], yet MRSA comprises less than half of all S. aureus infections. In day-to-day practice, clinicians rely on susceptibility results from the diagnostic microbiology laboratory to guide appropriate antimicrobial therapy for their patients. Most susceptibility tests performed in these laboratories rely on in vitro phenotypic methods, where the test organism is exposed to different concentrations of antibiotic and the impact on growth of the organism is determined. Performance and interpretation guidelines for these assays are provided by regulatory authorities such as the Clinical and Laboratory Standards Institute, and European Committee on Antimicrobial Susceptibility Testing. The minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial that will completely inhibit the growth of an organism after a defined period of incubation, usually 18 to 24 h, and is used by diagnostic microbiology laboratories to define antimicrobial susceptibility or resistance. All clinicians are aware, andmedical students are taught, not to use an antibiotic to treat a bacterial infection if the report from the microbiology laboratory indicates it is resistant to that antibiotic. There is, however, a limitation to the current methods for antimicrobial susceptibility testing—they are performed in vitro and therefore do not measure other potentially important factors influencing the in vivo activity of the agent. Aside from antibiotics, other significant contributors to the clearance of bacterial infections are the innate immune system factors including host defense peptides (HDPs) and neutrophils. Host defense peptides have received increasing attention in the scientific literature because of their antimicrobial activity against a wide range of pathogens, including drugresistant bacterial strains [4]. These amphipathic cationic peptides are naturally occurring antimicrobials produced by a variety of cell types such as epithelial cells and phagocytes [5], and while they have direct antimicrobial activity against human pathogens and cancer cells in vitro, they are increasingly recognized as important immunomodulators in vivo [6]. B. P. Howden (*) Austin Centre for Infection Research (ACIR), Infections Diseases Department, and Department of Microbiology, Austin Health, Heidelberg, Melbourne, Australia e-mail: Benjamin.Howden@austin.org.au