In vitro activity of oral antibiotics against extensively drug-resistant Shigella isolates: a pharmacokinetic/pharmacodynamic perspective on the intracellular pathogenesis paradigm

Introduction. Shigellosis is emerging as a critical therapeutic challenge in low- and middle-income countries (LMICs) due to the emergence of extensively drug-resistant (XDR) strains resistant to azithromycin, third-generation cephalosporins and fluoroquinolones. The obligate intracellular lifestyle of Shigella , characterized by epithelial cell invasion and actin-mediated intracellular spread, limits the predictive value of conventional extracellular susceptibility testing alone. Hypothesis/Gap Statement. The loss of effective oral antibiotics for XDR Shigella represents a major unmet clinical and public health need, particularly in endemic LMIC settings where outpatient management is essential. Current breakpoint-based susceptibility interpretations primarily reflect extracellular antimicrobial exposure and may inadequately capture the intracellular pharmacodynamic requirements of Shigella infection. Furthermore, integrated evaluation of in vitro susceptibility together with pharmacokinetic–pharmacodynamic (PK/PD) and intracellular exposure parameters for candidate oral agents against XDR Shigella remains limited. Aim. To evaluate the molecular resistance profiles, in vitro activity and PK/PD applicability of candidate oral antibiotics against XDR Shigella isolates. Methodology. Between 2010 and March 2025, 1,823 non-duplicate clinical Shigella isolates were screened at a tertiary care centre in South India. Fifty-two isolates fulfilled XDR criteria: azithromycin MIC ≥32 mg l −1 , ceftriaxone MIC >4 mg l −1 and ciprofloxacin MIC >1 mg l −1 . PCR assays targeted blaCTX-M , blaDHA , blaCMY , blaVIM , blaNDM , mphA , msrE , ermB , qnrS and qnrB . MICs for amoxicillin–clavulanate, cefpodoxime–clavulanate, fosfomycin, mecillinam and faropenem were determined using broth or agar dilution methods and interpreted using Clinical and Laboratory Standards Institute (CLSI) M100 (2025) or literature-derived PK/PD thresholds. Results. β -Lactamase genes and mphA were detected in 96.2% of isolates, whilst qnrS / qnrB occurred in 53.8%. Cefpodoxime–clavulanate and faropenem showed 100% susceptibility, followed by fosfomycin (98.1%) and mecillinam (94.2%). MIC50/MIC90 (mg l −1 ) were 0.5/0.5 for faropenem, 0.25/2 for mecillinam and 0.25/2 for cefpodoxime–clavulanate. However, PK/PD analysis suggested that several agents lacked sustained intracellular exposure despite favourable MICs. Conclusion. Favourable in vitro susceptibility did not consistently translate into predicted intracellular therapeutic adequacy. These findings support PK/PD-informed assessment beyond MIC-based interpretation for managing XDR shigellosis and highlight the urgent need for effective oral therapeutic options for XDR Shigella infections