Synergy in the Treatment of Severe Infections Caused by Extensively Drug-Resistant and Pandrug-Resistant Gram-Negative Bacteria: From the Checkerboard to the Bedside

Extensively drug-resistant (XDR) and pandrug-resistant (PDR) Gram-negative bacteria—principally carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Enterobacterales (CRE), and difficult-to-treat resistant (DTR) Pseudomonas aeruginosa—account for a growing share of severe nosocomial infections and rank among the pathogens of greatest public health concern. In the 2024 World Health Organization Bacterial Priority Pathogens List, CRAB and carbapenem-resistant Enterobacterales are classified as critical-priority pathogens and carbapenem-resistant P. aeruginosa as a high-priority pathogen, whereas difficult-to-treat resistance is a clinical resistance definition and not a WHO priority category. Because monotherapy is frequently inadequate or unavailable, combination regimens remain central to bedside decision-making, and antimicrobial synergy testing has moved from a niche laboratory exercise to a question with direct clinical relevance. This narrative review synthesises recent literature identified through a structured search, the preparation of which was guided by the SANRA quality criteria for narrative review articles. The synthesis is organised across four linked domains. First, the molecular mechanisms that determine which of the following combinations are rational: carbapenemase production, efflux- and porin-mediated impermeability, lipid A modification and polymyxin resistance, and iron-transport alterations underlying emerging cefiderocol resistance. Second, the laboratory methods used to detect synergy—the checkerboard assay and fractional inhibitory concentration index, time-kill assays, and dynamic pharmacokinetic/pharmacodynamic models, including the hollow-fibre infection model—and the genotype-dependence that limits their generalisability. Third, two agents whose combination behaviour is atypical: (1) cefiderocol, whose iron-transport-dependent uptake makes its synergy testing uniquely medium-dependent and for which pooled observational data in CRAB have reported lower mortality with monotherapy than with cefiderocol-containing combination regimens, although confounding by indication limits causal interpretation and (2) intravenous fosfomycin, whose unique MurA target and the risk of rapid resistance emergence during monotherapy often favour its use in combination regimens for severe MDR/XDR infections. Fourth, the clinical evidence from the ATTACK randomised trial of sulbactam-durlobactam in CRAB to large multicentre cohorts of ceftazidime-avibactam plus aztreonam in metallo-β-lactamase-producing Enterobacterales. We conclude that in vitro synergy testing retains clear value for individualising therapy when no single active agent can be identified, but that its translation to the bedside requires genotype-aware interpretation, pharmacokinetic or pharmacodynamic context, and corroboration against comparative clinical data rather than extrapolation from checkerboard results alone.