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From a strictly microbiological perspective, cross-resistance refers to a phenomenon in which resistance to different classes of antimicrobial agents arises due to a shared or overlapping resistance mechanism.1,2 Mechanisms such as broad-spectrum antibiotic-inactivating enzymes, ribosomal target-modifying enzymes, ribosomal mutations, and multidrug efflux pumps exemplify how a single bacterial resistance mechanism can reduce the efficacy of multiple, structurally unrelated antimicrobial agents.3 For example, macrolide, lincosamide, and streptogramin B (MLSB) antibiotics have distinct chemical structures but share a similar mode of action. Methylation of the A2058 residue in 23S rRNA, mediated by erm genes, or point mutations at position 2059, alters the antibiotic binding site and leads to cross-resistance to macrolides, lincosamides, and streptogramin B (MLSB phenotype) in Gram-positive cocci.4 Another example is the acquisition of the cfr (chloramphenicol–florfenicol resistance) gene, which encodes an rRNA methyltransferase that confers resistance to five antibiotic classes, including phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin A (PhLOPSA phenotype). PhLOPSA antibiotics bind near the peptidyl transferase center at A2503, however, cfr-mediated methylation at this site disrupts their binding.5 In Gram-negative bacteria, cross-resistance can also arise through mechanisms such as the production of AAC(6′)-Ib-cr, which is an aminoglycoside acetyltransferase that not only confers resistance to amikacin but also reduces the activity of ciprofloxacin by N-acetylating the amino nitrogen on its piperazinyl substituent.6 Other mechanisms include multidrug efflux pumps, which expel a broad range of antimicrobial agents in addition to disinfectants, heavy metals, and dyes, porin mutations that reduce antibiotic intake affecting a wide range of drugs, and the production of β-lactamases capable of hydrolyzing multiple β-lactam antibiotics, thereby contributing to cross-resistance within the β-lactam class.7,8 Unlike the microbiological concept of cross-resistance, based on defined mechanistic links, these epidemiological associations may be context-dependent and not universally applicable. For instance, in Pseudomonas aeruginosa, specific mutations in Pseudomonas-derived cephalosporinases (PDC, also referred to as AmpC) can result in resistance to ceftolozane-tazobactam and ceftazidime-avibactam, while simultaneously increasing susceptibility to imipenem.18 In contrast, the term collateral sensitivity has also been adopted in epidemiological contexts.14,15,19 Zwep and colleagues developed and implemented a statistical approach to detect collateral sensitivity and collateral resistance using large-scale clinical surveillance data.