Antimicrobial resistance is a serious global health threat, projected to cause up to 10 million deaths annually and substantial economic losses worldwide in the coming decades [[1], [2], [3]]. Among the pathogens listed by the World Health Organization as global priority bacterial pathogens for antimicrobial resistance, carbapenem-resistant Enterobacterales (CRE) are ranked among the top 3 organisms of critical concern [4]. Rising resistance to carbapenems has made Klebsiella pneumoniae (Kp) a major public health concern both in Türkiye and globally [5].

Despite the rising incidence of infections caused by carbapenemase-producing Kp (CP-Kp), the arsenal of effective antibiotics available for treatment continues to shrink [6]. The strategy of reserving newly developed antibiotics for last resort has inadvertently slowed progress in antimicrobial innovation [7]. Consequently, older antibiotics have regained clinical relevance. Parenteral fosfomycin (FOF) exhibits a unique mechanism of action, targeting the early stages of cell wall synthesis and remains active against multidrug-resistant Gram-negative and Gram-positive pathogens [8]. Because monotherapy carries a high risk of resistance emergence, particularly in invasive infections, FOF is generally used in combination regimens, which have demonstrated superior efficacy [9].

Previous studies have mainly focused on either the in vitro synergistic activity of FOF-based combinations (FOF-C) or their clinical outcomes in CP-Kp infections. However, data directly correlating in vitro synergy results with clinical outcomes remain limited. Furthermore, substantial heterogeneity in synergy testing methodologies, patient populations, infection sources, and underlying resistance mechanisms has hindered consistent interpretation and cross-study comparison.

Therefore, a comprehensive understanding of the clinical relevance of in vitro synergy remains limited, particularly for FOF-C. In this study, we evaluated the in vitro synergy of FOF combined with meropenem (MEM) and polymyxin (POL) – two commonly used agents against bloodstream infections (BSIs) caused by CP-Kp – using the checkerboard (CB) method, and analysed the associated clinical outcomes.