Advances and updates in antibiotic combination therapy

Abstract

Introduction: While antibiotic combination therapy remains a common clinical practice, its scientific foundation is fragile. The available evidence is fragmented, biased, and fails to capture the complexity of modern infectious disease scenarios. This perspective reinterprets the role of combination therapy through a critical lens, challenging current dogmas and proposing a pathogen-specific approach, focusing also on severe acute infections. Areas covered: This Critical Perspective focused on selected studies from 2018 to 2025 identified through a focused PubMed search on the place in therapy and efficacy of antibiotic combinations on main gram-positive (Streptococcus spp. Enterococcus spp. and Staphylococcus aureus) and gram-negative (Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia) pathogens. Expert opinion: After reviewing the current available literature, in our opinion, a strong indication to use antibiotic combination therapy can be only for specific situations and clinical syndromes (such as endocarditis, toxic shock syndrome due to S. pyogenes, or persistent bacteremia due to S. aureus and few others). However, especially in severe infections due to gram negatives, clinical trial and strong data are insufficient to draw definite clinical indications. Consequently, further randomized clinical trial should be performed, and they should include new antibiotics to define the potential role of combination therapy.