In vitro Synergy Testing of Daptomycin with Beta-lactams, Gentamicin, Rifampin and Tigecycline against Daptomycin Non-Susceptible Enterococci
Combination therapy is an important consideration for treatment of daptomycin (DAP) non susceptible Enterococcus (DNSE) infections. There are limited in vitro or in vivo data regarding possible synergy between DAP with other antimicrobials against DNSE.
In vitro synergy testing of DAP with eight antimicrobials [ampicillin (AMP), cefazolin (CFZ), ceftriaxone (CRO), ceftaroline (CTL), ertapenem (ERT), gentamicin (GEN), rifampin (RIF), tigecycline (TGC)] was performed using time-kill assays against 9 unique isolates of DNSE [DAP MIC 24 - >256 ug/mL, determined by broth microdilution]. Change in colony-forming units per ml (CFU/ml) over 24-h antimicrobial exposures for DAP alone or in combination were evaluated by kill curve. Synergy was defined as ≥2 log10 reduction in CFU/ml at 24 h with the combination, as compared to DAP or the test antimicrobial alone. Two different DAP concentrations were tested: 0.5X the DAP MIC for each isolate; and 180 ug/ml, the maximal achievable serum DAP concentration (Cmax) corresponding to a DAP dose of 12 mg/kg/d. All other agents were tested at their respective Cmax, based on routine dosing.
Two E. faecalis and 7 E. faecium were tested. AMP, CTL, ERT showed the greatest synergy with DAP against DNSE (Figure 1). Figure 2 shows the change in CFU/mL after 24-h antimicrobial exposures for test antimicrobial alone or in combination with DAP (at Cmax) for 2 isolates that displayed growth after 24 h incubation at the DAP Cmax. For 7 isolates that did not grow under these conditions, DAP (at Cmax) in combination with TGC and RIF displayed antagonism for 2 and 5 isolates, respectively. No trends were noted in results between E. faecalis and E. faecium, nor between isolates with high-level resistance (>256 µg/mL) and lower DAP MICs.
Time-kill assays revealed synergy for the DAP-AMP combination in 6/7 DNSE isolates at 0.5X the DAP MIC and for both DNSE isolates that grew at the DAP Cmax. DAP also had synergy with all 5 beta-lactams tested and GEN against 22-56% of DNSE isolates. Since combinations of DAP with antimicrobials may display indifference or antagonism, further studies are needed to determine the potential usefulness of combinations of DAP with other agents for treatment of DNSE infections.
A. Wong-Beringer, None
M. Carvalho, None
M. Maldonado, None
R. M. Humphries, Affinity Biosensors: Investigator, Research support