Antimicrobial Efficacy against Antibiotic-Tolerant Staphylococcus aureus Depends on the Mechanism of Antibiotic Tolerance

Abstract

Bacteria can adapt to a changing environment by adopting alternate metabolic states favoring small molecule synthesis and resilience over growth. In Staphylococcus aureus, these states are induced by factors present during infection, including nutritional limitations, host responses and competition with other bacteria. Isogenic "tolerant" populations have variable responses to antibiotics and can remain viable. In this study, we compared the capability of antibiotics to reduce the viability of S. aureus made tolerant by different mechanisms. Tolerance was induced with mupirocin, HQNO, peroxynitrite or human serum. Tolerant cultures were exposed to ceftaroline, daptomycin, gentamicin, levofloxacin, oritavancin or vancomycin at physiological concentrations, and the viability was assessed by dilution plating. The minimum duration for 3-log viability reduction and 24 h viability reduction were calculated independently for each of three biological replicates. Each tolerance mechanism rendered at least one antibiotic ineffective, and each antibiotic was rendered ineffective by at least one mechanism of tolerance. Further studies to evaluate additional antibiotics, combination therapy and different tolerance inducers are warranted.

Keywords: MRSA; Staphylococcus aureus; persistence; tolerance.

Figure 1

Activity of study antibiotics against induced-tolerant staphylococci determined in Mueller–Hinton broth. (A) ceftaroline; (B) daptomycin; (C) gentamicin; (D) levofloxacin; (E) oritavancin; and (F) vancomycin. Dotted line with black points, nutritional tolerance; dashed line with gray points, oxidative tolerance; solid line with white points, competitive tolerance; and gray line without points, no tolerance induction.

Figure 1

Activity of study antibiotics against induced-tolerant staphylococci determined in Mueller–Hinton broth. (A) ceftaroline; (B) daptomycin; (C) gentamicin; (D) levofloxacin; (E) oritavancin; and (F) vancomycin. Dotted line with black points, nutritional tolerance; dashed line with gray points, oxidative tolerance; solid line with white points, competitive tolerance; and gray line without points, no tolerance induction.

Figure 2

Activity of study antibiotics against induced-tolerant staphylococci determined in human serum. (A) ceftaroline; (B) daptomycin; (C) gentamicin; (D) levofloxacin; (E) oritavancin; and (F) vancomycin. Dotted line with black points, bacteria conditioned overnight in serum prior to antibiotic exposure; and gray line without points, bacteria inoculated into serum immediately prior to antibiotic exposure.