Due to convenient dosing, ceftriaxone (CRO) is used as out-patient antimicrobial therapy (OPAT) even when broad coverage is not required. Its use to treat MSSA infections is largely accepted based on high susceptibility rates. With actual MIC distributions, however, the activity of CRO may be inadvertently reduced especially with once-daily dosing. Our goal was to use an integrated pharmacokinetic-pharmacodynamic (PKPD) analysis to study CRO and alternatives in OPAT for MSSA infections.
Methods: Monte Carlo simulation was used to create cohorts of 5 000 subjects. CRO, cefazolin (CFZ) and, if contraindicated, alternatives such as vancomycin (VAN), linezolid (LZD) and daptomycin (DAP) were tested using published PK models to simulate free (ƒ) plasma concentrations in a relevant patient population (75 ± 10 kg, Clcr 50 to 100 mL/min/72 kg). Robust MIC distributions were based on data from 6 490 MSSA isolates collected from 13 Canadian hospitals (2007–2015). Predicted target attainment for CRO and CFZ was % of simulated subjects that achieved >55%ƒT>MIC (stasis), >75%ƒT>MIC (1–2 log kill) and 100%ƒT>MIC (cidal) based on literature values and our previous in vitro PD modeling studies. PD targets for the alternatives were AUC/MIC >400 for VAN, >80 for LZD and >400–800 for DAP. Cumulative target attainment (CTA) was considered optimal when PD targets were achieved in >90% of subjects.
Results: The mean PK parameters were CRO (Vd 12.8 L, t½ 9.2 h), CFZ (Vd 11.3 L, t½ 3.2 h), VAN (CL 4.5 L/h), LZD (CL 6.8 L/h), DAP (CL 0.8 L/h), and MIC distributions (MIC50, MIC90) were CRO (4, 4 mg/L), CFZ (0.5, 1 mg/L), VAN (1, 1 mg/L), LZD (2, 2 mg/L), DAP (0.25, 0.25 mg/L). Optimal CTA for stasis required twice-daily CRO, but was achieved with once-daily CFZ. CRO 2 g q24h reached PD targets for stasis, 1–2 log kill and cidal activity in 86%, 46% and 17% of simulated subjects, respectively, whereas CFZ 2 g q24h attained these targets in 96%, 50% and 15% of cases. For the alternatives, AUC/MIC targets were achieved in 81% and 100% of subjects with VAN 1 g q12h and 1.5 g q12h, respectively, in 77% of cases with LZD 600 mg q12h and in 96% with DAP 4 mg/kg q24h.
Conclusion: Based on actual MIC distributions of MSSA, the predicted PD activity of once-daily CRO was lessened and actually inferior to once-daily CFZ. These findings highlight the limitations of CRO in OPAT for MSSA infections.