307 - Rapid Resistance Development to Three Antistaphylococcal Therapies in Daptomycin-tolerant Staphylococcus aureus Bacteremia

Background: We report a patient case of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia which over 30 days developed resistance to all three primary antistaphylococcal antibiotics. Index blood cultures displayed susceptibility to vancomycin (VAN, MIC=1), ceftaroline (CPT, MIC=0.5) and daptomycin (DAP, MIC=0.5). The patient was maintained on VAN/CPT with negative blood cultures by hospital day 7. The regimen was later modified to DAP/piperacillin-tazobactam. One month after initial presentation, during the same encounter, blood cultures were again positive for MRSA, now displaying intermediate resistance to VAN (MIC=2) and CPT (MIC=2), and resistance to DAP (MIC=4).

Methods: Isolates were collected from the initial bacteremia episode (B325) and the recurrence (B326). In-vitro one-compartment pharmacokinetic/pharmacodynamic modeling was performed on each isolate to determine which antibiotics or combinations would effectively eradicate cultures. Regimens examined included DAP (10mg/kg), DAP/cefazolin (CFZ), VAN/CFZ and penicillin/clavulanate. Draft whole-genome sequences are pending for each clinical isolate using hybrid assembly (Unicycler v0.4.2) of MinION and Illumina (150bp PE) reads.

Results: DAP/CFZ combination reduced viability of both B325 and B326 below limit of detection by 12 hours and maintained efficacy for 72 h. DAP, initially effective in reducing B326 cell concentrations below limit of detection, allowed regrowth by 36 h. All other modeled therapies were less effective. Interestingly, DAP took significantly longer to kill B325 relative to S. aureus collected contemporaneously from other patients. For DAP-containing regimens, the time to 3-log viability reduction (MDK_99.9) was five-fold longer in B325 compared to similar clinical isolates with the same DAP MIC. Comparative genomics of sequential isolates is pending, although single nucleotide polymorphisms in vraT and mprF were identified in B326 compared to B325.

Conclusion: Delayed kill kinetics of B325 when exposed to DAP may indicate antibiotic tolerance, which could partially account for B325’s rapid transition to a multi-drug resistant organism. DAP/CFZ therapy appears to be the most active combination against both antibiotic-tolerant and multidrug resistant S. aureus strains.