1606 - Distinct Effectiveness of Oritavancin Against Tolerance-Induced Staphylococcus aureus

Background: Within a sufficiently large bacterial population, some members will naturally adopt an alternate, metabolically-active state that favors small molecule synthesis over cell division. In Staphylococcus aureus this process can be sharply accelerated by multiple factors present during infection including nutrient limitation, host cationic peptide exposure and polymorphonuclear neutrophil internalization. These isogenic “tolerant” subpopulations have variable responses during antibiotic exposure and can remain viable in the presence of typically bactericidal concentrations. Survivors of antibiotic exposure can restart cell division upon cessation of antibiotics and cause relapse or recurrent infection. In this study we determine the ability of typical and atypical antistaphylococcal therapies to reduce the viability of tolerant Staphylococcus aureus bacteria.

Methods: S. aureus strain ATCC29213 as well as four clinical isolates (two MSSA, two MRSA) were selected for analysis. Overnight cultures were diluted in pre-warmed broth (MHB50) to 1×10⁶ cfu/mL. Tolerance was induced by exposure to mupirocin (low [0.032 µg/mL] or high [3.2 µg/mL]) for 30 min. Tolerant cultures were exposed to vancomycin (35 µg/mL), cefazolin (25 µg/mL), daptomycin (7 µg/mL), telavancin (10 µg/mL), dalbavancin (6 µg/mL) or oritavancin (14 µg/mL) and viability was assessed by dilution plating at pre-defined time points (0, 2, 6, 24, 48 h). The minimum duration for 3-log viability reduction from baseline (MDK_99.9) and culture viability at 48h were calculated independently for each of three biological replicates.

Results: The rate of bacterial killing (MDK_99.9) was reduced for all study antibiotics by the addition of mupirocin in a dose-dependent manner. In contrast to all other regimens, including lipoglycopeptide comparators, oritavancin was the only antimicrobial agent that maintained a similar extent of bacterial killing against tolerant staphylococci.

Conclusion: Antimicrobial tolerant staphylococci exhibit a decreased rate of killing by antistaphylococcal agents. However, oritavancin remained effective at maintaining a similar extent of killing. Further studies to investigate the role of otritavancin against recurrent or relapse staphylococcal infection is warranted.