Abstract
Background
Previous studies demonstrate that adding oxacillin during daptomycin (DAP) exposure can prevent DAP resistance development in community-acquired (ST8/USA300) MRSA, presumably by preventing mprF mutation. Hospital-acquired strains, such as MRSA sequence types 5 and 239, typically have higher β-lactam (BL) minimum inhibitory concentrations (MICs) than their community-acquired counterparts and are often less toxigenic, more multidrug-resistant and more refractory to primary antistaphylococcal therapies. It is unknown whether DAP resistance prevention occurs in hospital-acquired MRSA lineages or if augmenting DAP therapy with BL antibiotics other than oxacillin would prevent DAP resistance development.
Methods
MRSA ST5/USA100 (D592) and ST239 (JKD6004) differ in the degree to which BL enhances DAP activity. D592 and JKD6004 were passaged in escalating concentrations of DAP in a stepwise fashion in vitro as described previously. Following 28 days of serial passage all replicates were passaged twice on mannitol-salt agar and tested for DAP MIC by Etest. Parallel passages were performed in media supplemented with BL antibiotics. Between-group differences in DAP MIC suppression effectiveness among individual BLs compared with nafcillin was evaluated using Kruskal–Wallis rank-sum testing with Holm-adjusted post-hoc Dunn testing.
Results
Passage of D592 or JKD6004 in DAP resulted in highly DAP-resistant isolates (median ≥256 mg/L, IQR [96,256]). In contrast, when passages were performed in the presence of DAP+BL, DAP resistance development was suppressed. No between-group differences in DAP MIC suppression effectiveness were observed among individual BLs compared with nafcillin. Highly DAP-resistant isolates demonstrated variable collateral susceptibility to BL monotherapy but were frequently susceptible to combination antibiotic exposure.
Conclusion
Addition of β-lactams to DAP can prevent DAP resistance development in vitro in ST5/USA100 and ST239 MRSA, consistent with findings in ST8/USA300 lineages. Furthermore, this ability appears to be a class effect of β-lactam antibiotics and is independent of the extent of DAP-BL synergy. This provides evidence to support the use of BL combination therapy without regard to staphylococcal lineage or specific BL used.
Disclosures
All authors: No reported disclosures.
Session: 65. Mechanisms of Antimicrobial Resistance
Thursday, October 3, 2019: 12:15 PM