# Pharmacokinetic/Pharmacodynamic Analysis of High-Dose Daptomycin in Combination with Continuous Infusion Ceftobiprole in a Case Series of Documented Staphylococcal Bacteremia or Endocarditis: Is There Any Room for TDM-Guided Dosing Reduction?

## TL;DR

This study evaluates the effectiveness and safety of combining high-dose daptomycin with ceftobiprole for treating staphylococcal bloodstream infections and endocarditis, finding that drug monitoring can help optimize dosing.

## Contribution

The study demonstrates the feasibility of therapeutic drug monitoring-guided dose adjustments in a daptomycin-ceftobiprole combination therapy for staphylococcal infections.

## Key findings

- Daptomycin and ceftobiprole combination achieved high PK/PD target attainment in most patients.
- Clinical cure rates were 77.8% for BSI and 91.7% for IE.
- Dose de-escalation was frequently possible without compromising efficacy.

## Abstract

Background: Staphylococcal bloodstream infections (BSIs) and infective endocarditis (IE) are associated with high morbidity and mortality. Among the different antimicrobial combination strategies proposed to enhance antibacterial activity, the association of daptomycin and ceftobiprole may be valuable. The aim of this study was to assess the PK/PD target attainment, safety, and clinical outcomes of such combination therapy for BSI and IE treatment. Methods: This retrospective monocentric study included adult patients with targeted treatment of staphylococcal BSI or IE with daptomycin plus continuous infusion (CI) ceftobiprole. Therapeutic drug monitoring (TDM) was performed for both agents, including Bayesian estimation of daptomycin 24 h area under the concentration–time curve (AUC24h). PK/PD targets were defined as daptomycin AUC24h/MIC ≥ 666 and ≥1081, and ceftobiprole steady-state concentration/MIC ≥ 4. Dose adjustments, safety, microbiological response, and clinical outcomes were assessed. Results: Twenty-three patients (11 BSI and 12 IE) were included. Methicillin-resistant Staphylococci were identified in 91.3% of cases. At first TDM assessment, daptomycin PK/PD targets were achieved in all patients, while ceftobiprole targets were achieved in 91.6% of BSI cases and in all IE cases. PK-/PD-guided dose de-escalation was frequently feasible. Clinical cure was observed in 77.8% of evaluable patients with BSI and in 91.7% with IE. Creatine phosphokinase elevations occurred in two patients, while hyper-eosinophilia was observed in 69.6% and was manageable with monitoring. Conclusions: Targeted therapy with daptomycin plus CI ceftobiprole achieved high PK/PD target attainment and favorable clinical outcomes in staphylococcal BSI and IE. TDM and model-informed precision dosing may enable dose optimization and may improve the balance between efficacy and safety. Multicenter studies are warranted.