Cefiderocol Heteroresistance in NDM-Producing Enterobacterales: A Complex Polymicrobial Infection Successfully Salvaged With Ceftazidime-Avibactam Plus Aztreonam.

BACKGROUND Heteroresistance among New Delhi metallo-ß-lactamase (NDM)-producing carbapenem-resistant Enterobacterales (CRE) is an emerging but underrecognized mechanism of treatment failure. Although cefiderocol is a preferred therapy for metallo-ß-lactamase-producing organisms, real-time development of discordant susceptibility within the same patient remains rarely described. We present a case demonstrating site-specific cefiderocol heteroresistance with divergent microbiologic responses, highlighting critical diagnostic and therapeutic implications. CASE REPORT A 64-year-old woman developed a prolonged polymicrobial prosthetic joint infection following left total knee arthroplasty, initially involving Candida albicans, Acinetobacter baumannii, and Stenotrophomonas maltophilia, later evolving into disseminated infection with NDM-producing Klebsiella pneumoniae and Enterobacter cloacae. Despite multiple surgical debridements and prolonged antimicrobial therapy, she presented with septic shock and respiratory failure. Empiric cefiderocol therapy was initiated; however, simultaneous isolates from different anatomical sites demonstrated discordant susceptibility, with cefiderocol resistance emerging in respiratory isolates while wound isolates remained susceptible, consistent with heteroresistant subpopulations. Advanced microbiologic evaluation confirmed synergy with ceftazidime-avibactam plus aztreonam, prompting therapeutic transition. Given her progressive necrotizing infection and uncontrolled source burden, a left above-knee amputation was performed, after which the patient achieved clinical stabilization. CONCLUSIONS This case uniquely illustrates real-time cefiderocol heteroresistance with site-specific susceptibility divergence in NDM-producing CRE, emphasizing the limitations of single-site susceptibility testing and the necessity for repeat and multi-site antimicrobial evaluation during therapy. Early recognition of heteroresistant subpopulations, incorporation of advanced microbiologic testing, and timely escalation to ceftazidime-avibactam plus aztreonam are critical for managing high-risk multidrug-resistant infections. The case highlights the evolving complexity of CRE treatment and the potential for catastrophic clinical outcomes despite novel antimicrobial therapy.