PK/PD Analysis of Ceftazidime/Avibactam or Cefiderocol With or Without Fosfomycin for the Treatment of Difficult To-treat Gram-negative Infections

Gram-negative infections, particularly those caused by Carbapenem-resistant Enterobacterales (CRE), have a dramatic impact on patient survival. Despite the introduction of new drugs in the last years have improved the outcome of patients with difficult-to-treat gram-negative infections, mortality and relapse rates are still relevant, especially in patients with high-risk sources such as pneumonia, and those in which the attainment of optimal exposure could be reduced by underlying renal disease. The use of a combination regimen in these scenarios has been proposed. However, a standardized approach to therapeutic management is still missing. To overcome this unmet clinical need, this study aims to investigate the pharmacokinetic/pharmacodynamics (PK/PD) optimization of antibiotic dosing regimens in patients with difficult-to-treat Gram-negative infections, using Therapeutic Drug Monitoring (TDM). A prompt implementation of an appropriate targeted antibiotic therapy could represent a valuable approach to improve clinical outcomes in patients with difficult-to-treat Gram-negative infections. Moreover, more information is needed in pediatric populations where ceftazidime/avibactam (CAZ/AVI) is approved only for children aged > 3 months (with the same indications as adults) and cefiderocol (CEF) is not approved. Indeed, cefiderocol is currently off-label administered in pediatric population using case-by-case dosages based on encouraging case reports.

Since several in vitro studies have highlighted the synergistic effect of fosfomycin (FOS) with different antibiotic classes, including cephalosporins such drug could be an appealing option in combination therapy for the management of difficult-to-treat gram-negative infections, both with CAZ/AVI and CEF. However, real-life prospective studies are needed to investigate the potential benefit of combination therapy on clinical outcomes and the occurrence of further resistance. Thus, the correct dose of FOS along with the type of administration (i.e., intermittent, extended, or continuous infusion) are issues to establish.

In particular, the primary aim of the study is to evaluate the probability of achieving pre-determined pharmacokinetic/pharmacodynamic (PK/PD) efficacy targets for CAZ/AVI, CEF and FOS.

Secondary objectives are:

• to evaluate the relationship between the achievement of the PK/PD target of CAZ/AVI, CEF and FOS and microbiological eradication;

• to evaluate the trend of clinical biomarkers in response to antibiotic therapy;

• to investigate the diagnostic and prognostic value of protein biomarkers.

This research is supported by EU funding within the Next Generation EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT).