Evolution of β-Lactam Antibiotic Resistance in Proteus Species: From Extended-Spectrum and Plasmid-Mediated AmpC β-Lactamases to Carbapenemases

The management of infectious diseases has proven to be a daunting task for clinicians worldwide and the rapid development of antibiotic resistance among Gram-negative bacteria is making it even more challenging. The first-line therapy is empirical and it most often comprises β-lactam antibiotics. Among Gram-negative bacteria Proteus mirabilis, important community and hospital pathogen associated primarily with urinary tract and wound infection, holds a special place. This review’s aim was to collate and examine recent studies investigating resistance phenotypes and mechanisms of Proteus species and the global significance of its resistance evolution. P. mirabilis as the dominant pathogen develops resistance to expanded-spectrum cephalosporins (ESC) by producing extended-spectrum β-lactamases (ESBL) and plasmid-mediated AmpC β-lactamases (p-AmpC). β-lactamase-mediated resistance to carbapenems in Enterobacterales including Proteus spp. is mostly due to expression of carbapenemases of class A (KPC), class B (metallo-β-lactamases or MBLs of IMP, VIM or NDM series) or class D or carbapenem-hydrolyzing oxacillinases (CHDL). Previously, a dominant ESBL type in P. mirabilis was TEM-52, yet lately it has been replaced by CTX-M variants, particularly CTX-M-3 and CTX-M-65. ESC resistance can also be mediated by p-AmpC with CMY-16 as the dominant variant. Carbapenem resistance in Proteus spp. is a challenge due to its intrinsic resistance to colistin and tigecyclin. The first carbapenemases reported, belonged to class B, most frequently VIM-1 and NDM-5. In Europe, predominantly France and Belgium, a clonal lineage positive for OXA-23 CHD spread rapidly undetected, due to its low-level resistance to carbapenems. Amazing capacity of Proteus spp. to accumulate a plethora of various resistance traits leading to multidrug or extensively- drug- resistant phenotype.