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To discuss empirical therapy for severe infections due to Gram-negative bacteria with difficult-to-treat resistance (GNB-DTR) in current clinical practice, focusing in particular on the positioning of novel therapeutic agents and rapid diagnostic tests.The current era of novel agents active against GNB-DTR and showing differential activity against specific determinants of resistance is an unprecedented scenario, in which the clinical reasoning leading to the choice of the empirical therapy for treating severe GNB-DTR infections is becoming more complex, but it also allows for enhanced treatment precision.Novel agents should be used in line with antimicrobial stewardship principles, aimed at reducing selective pressure for antimicrobial resistance. However, this does not mean that they should not be used. Indeed, excesses in restrictive uses may be unethical by precluding access to the most effective and less toxic treatments for patients with severe GNB-DTR infections. Given these premises (the 'how'), empirical treatment with novel agents should be considered in all patients with risk factors for GNB-DTR and severe clinical presentation of acute infection (the 'when'). Furthermore, empirical novel agents should preferably be continued only for a few hours, until de-escalation, modification, or confirmation (as targeted therapy) is made possible by the results of rapid diagnostic tests (the 'how long').

Purpose of review To summarize the available results of primary analyses from high-quality randomized studies of either recently approved or possible future agents for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Recent findings In the last 2 decades, several novel agents have been approved for the treatment of ABSSSI, that are also active against methicillin-resistant Staphylococcus aureus (MRSA). In addition to already available agents, further molecules are in clinical development that could become available for treating ABSSSI in the forthcoming future. Summary The current and future availability of several new-generation antibiotics will allow to modulate therapeutic choices not only on efficacy but also on other relevant factors such as the combination of the drug safety profile and the comorbidities of any given patient, the expected adherence to outpatient therapy, and the possibilities of early discharge or avoiding hospitalization by means of oral formulations, early switch from intravenous to oral therapy, or single-dose administration of long-acting intravenous agents. With the advent of new-generation antibiotics, all these factors are becoming increasingly essential for tailoring treatment to individual patients in line with the principles of personalized medicine, and for optimizing the use of healthcare resources.