Adjunctive protein synthesis inhibitor antibiotics for toxin suppression in Staphylococcus aureus infections: A systematic appraisal

Abstract

Staphylococcus aureus is a Gram-positive bacteriumthat is among the most common pathogens in humans causing a broad spectrum of clinical manifestations.1 Its ability to express multiple extracellular toxins, including haemolysins, leukotoxins, exfoliative toxins, enterotoxins and toxic shock syndrome toxin-1 (TSST-1), which destroy host cells and circumvent host immune defence mechanisms, contribute to its success as a pathogen.2 Treatment of S. aureus infection routinely relies on cell-wall-active antibiotics, including b-lactams and glycopeptides, which do not attenuate toxin production. Indeed, in vitro and animal studies have demonstrated that b-lactams (at subinhibitory concentrations) can increase S. aureus toxin production3-5 and vancomycin has minimal effect (Figure 1).3,4 The principal protein synthesis inhibitor (PSI) antibiotics that are active against S. aureus and reduce bacterial toxin production are clindamycin and linezolid. Other PSI antibiotics with antistaphylococcal activity include macrolides, chloramphenicol, fusidic acid and streptogramins (quinupristin/dalfopristin, pristinamycin), which all bind to the 50S ribosomal subunit, interfering with its functions of controlling guanosine triphosphate hydrolysis, the formation of peptide bonds and channelling the peptide through the subunit tunnel. Tetracyclines, tigecycline and aminoglycosides are PSI antibiotics that all bind to the 30S subunit and interfere with the principal function of decoding mRNA to peptides (Figure 1).3,6 Whilst the antibiotic mechanism of action has been established, evidence is conflicting regarding the mechanism of action (transcription, translation or both) PSIs have on toxin production.3,7 The resulting impact that antibiotic resistance has on S. aureus toxin production in laboratory in vitro studies is also inconsistent.8,9 The addition of a PSI antibiotic to standard therapy (cell-wallactive antibiotic) may be used in the treatment of S. aureus infections to: broaden coverage during empirical therapy; achieve synergy; enhance tissue biofilm penetration; or limit toxin production.10 This review summarizes the current, available evidence on combination antibiotic therapy for suppression of toxin synthesis in the treatment of S. aureus infections, with a focus on the PSI antistaphylococcal antibiotics for which there is the most evidence, namely clindamycin, linezolid and gentamicin.