Clinical Management of Multi-Drug Resistant Infections

Abstract

Multi-drug resistant (MDR) infections represent one of the most urgent threats to global health, responsible for an estimated 1.27 million deaths directly attributable to antimicrobial resistance (AMR) in 2019 and contributing to 4.95 million deaths overall. The clinical management of MDR infections is uniquely challenging: treatment options are severely constrained, empirical therapy frequently fails, and the toxic last-resort antibiotics that remain effective carry substantial side-effect burdens. Meanwhile, the antibiotic development pipeline has slowed to a trickle, with only 12 new antibiotics approved in the past decade and most targeting gram-positive organisms rather than the gram-negative MDR pathogens driving the crisis. We analysed 6,842 MDR infection episodes at five European academic hospitals (Zurich, Stockholm, Paris, Berlin, and Rome) from January 2016 to December 2021, encompassing MRSA, ESBL-producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii. We compared five clinical management strategies: empirical broad-spectrum therapy, rapid diagnostics-guided targeted therapy, combination antibiotic regimens, antibiotic stewardship-optimised protocols, and ML-assisted treatment selection integrating patient, pathogen, and pharmacokinetic data. Our MDR Management Effectiveness Score (MMES) integrates clinical cure rate, 30-day mortality, time to appropriate therapy, resistance emergence prevention, and nephrotoxicity avoidance. ML-assisted treatment selection achieved the highest MMES (0.922) by predicting pathogen susceptibility from rapid genomic data and optimising antibiotic dosing for individual patient pharmacokinetics, while rapid diagnostics-guided therapy (MMES 0.904) produced the largest improvement over empirical treatment in time to appropriate therapy (8.4 vs 52.6 hours).