The most important multiresistant bacteria causing treatment failures are extended-spectrum β-lactamase and/or plasmid-mediated AmpC β-lactamase positive Enterobacteriaceae, carbapenemase producing Acinetobacter baumannii and Pseudomonas (P.) aeruginosa, methicillin-resistant Staphylococcus (S.) aureus, penicillin-resistant Streptococcus pneumoniae, and van-comycin- resistant Enterococcus spp. Extended-spectrum β-lactamases hydrolyze oxyimino-caphalosporins and aztreonam, are mostly produced by Enterobacteriaceae, and are encoded on transferable plasmids which often contain resistance genes to non-􀁠-lactam antibiotics. Plasmid-mediated AmpC β-lactamases descend from the chromosomal ampC gene transferred to the plasmid. Those 􀁠-lactamases confer resistance to first, second and third generation of cephalosporins, monobactams, and to 􀁠-lactam-􀁠-lactamase inhibitor combinations. Enterobacteriaceae may develop resistance to carbapenems due to the hyperproduction of ESBLs or plasmid-mediated AmpC β-lactamases in combination with porin loss or due to the production of carbapenemases of class A (KPC, IMI, NMC, SME), B (metallo-β-lactamases from VIM, IMP or NDM series), and D (OXA-48 β-lactamase). Carbapenemases found in Acinetobacter spp. belong to molecular class A (KPC), B (metallo-β-lactamases of IMP, VIM, NDM or SIM family) and D (OXA enzymes). The most frequent mechanism of carbapenem resistance in Acinetobacter spp. is through the production of OXA-enzymes but other various mechanisms including decreased permeability and efflux pump overexpression could also be involved. Carbapenem-resistance in P. aeruginosa is usually mediated by the production of metallo-β-lactamases of IMP, VIM, GIM, SPM or NDM series, loss of OprD outer membrane protein and/or upregulation of MexAB or MexCD efflux pumps. Methicillin-resistance in S. aureus occurs as the result of the acquisition of mecA gene that encodes novel PBP2a protein. Expression of PBP2a renders bacteria resistant to all 􀁠-lactams including cephalosporins (with the exception of ceftaroline and ceftobiprole) and carbapenems. Most strains of penicillin resistant Streptococcus pneumoniae are often resistant to cephalosporins and antibiotics from other classes, presenting a serious problem in treating invasive infections. The most important therapeutic problem in enterococci is development of resistance to vancomycin.