Beyond susceptibility: pharmacokinetic and pharmacodynamic constraints of existing oral antibiotics in extensively drug-resistant typhoid fever

Abstract Salmonella Typhi is an invasive pathogen with sustained bacteraemia and intracellular persistence, requiring therapy that achieves systemic exposure and intracellular penetration. Clinical efficacy should remain central to therapeutic decision-making, while pharmacokinetic/pharmacodynamic (PK/PD) analyses provide complementary insights into dose optimization and the pharmacological limitations of candidate therapies. Oral therapy remains central to typhoid fever management, particularly in South and Southeast Asia, where most patients are managed in the outpatient setting. However, the emergence of MDR and extensively drug-resistant (XDR) S. Typhi has substantially narrowed the available oral treatment options. Azithromycin remains the only widely available oral agent with established clinical efficacy, but emerging resistance threatens its continued utility. Several alternative oral agents, including mecillinam, faropenem, tebipenem, fosfomycin and β-lactam/β-lactamase inhibitor combinations, demonstrate favourable in vitro activity against S. Typhi. However, robust clinical efficacy and contemporary PK/PD data are lacking to support their use against MDR and XDR S. Typhi. Addressing these evidence gaps through integrated PK/PD investigations and prospective clinical trials will be essential to expand the oral therapeutic armamentarium for typhoid fever.