Pharmacodynamics of Ceftriaxone and Alternatives as Outpatient Antimicrobial Therapy for Methicillin-Susceptible Staphylococcus aureus Infections
Bibliographic record
Abstract
Background. Due to convenient dosing, ceftriaxone (CRO) is used as outpatient antimicrobial therapy (OPAT) even when broad coverage is not required. Its use to treat methicillin-susceptible Staphylococcus aureus (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 5000 subjects. The 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 6490 MSSA isolates collected from 13 Canadian hospitals (2007–2015). Predicted target attainment for CRO and CFZ was percentage 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. Ceftriaxone 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. Disclosures. All authors: No reported disclosures.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".