Mechanisms of Antibiotic Resistance in Important Gram-Positive and Gram-Negative Pathogens and Novel Antibiotic Solutions

Abstract

Multidrug-resistant bacteria have on overwhelming impact on human health, as they cause over 670,000 infections and 33,000 deaths annually in the European Union alone. Of these, the vast majority of infections and deaths are caused by only a handful of species-multi-drug resistant Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus spp., Acinetobacter spp. and Klebsiella pneumoniae. These pathogens employ a multitude of antibiotic resistance mechanisms, such as the production of antibiotic deactivating enzymes, changes in antibiotic targets, or a reduction of intracellular antibiotic concentration, which render them insusceptible to multiple antibiotics. The purpose of this review is to summarize in a clinical manner the resistance mechanisms of each of these 6 pathogens, as well as the mechanisms of recently developed antibiotics designed to overcome them. Through a basic understanding of the mechanisms of antibiotic resistance, the clinician can better comprehend and predict resistance patterns even to antibiotics not reported on the antibiogram and can subsequently select the most appropriate antibiotic for the pathogen in question.

Keywords: Acinetobacter baumannii; Enterococcus faecalis; Enterococcus faecium; Escherichia coli; Klebsiella pneumoniae; MRSA; Pseudomonas aeruginosa; Staphylococcus aureus; VRE; multi-drug resistant infections.

Figure 1

The Ambler classification of β-lactamases, which is based on each enzyme’s primary protein structure. The active site of enzymes of Classes A, C, D contains a serine residue, which is necessary for the hydrolysis of the beta-lactam ring, while enzymes of Class B require zinc ion cofactor in order to function (thus termed metallo-β-lactamases) [3,4]. Abbreviations: ESBL: extended spectrum β-lactamase; TEM, Temoniera; SHV, sulfhydryl variable; CTX-M, Cefotaxime β-lactamase; KPC, Klebsiella pneumoniae Carbapenemase; OXA, oxacillinase; IMP, Imipenemase type carbapenemase; NDM-1, New Delhi metallo-β-lactamase; VIM, Verona integron-encoded metallo-β-lactamase.

Figure 2

The degradation pattern for each type of β-lactamase. Cefoxitin is displayed differently from other 2nd generation cephalosporins, as hydrolysis of cefoxitin can be used to differentiate AmpC (hydrolyzes cefoxitin) from ESBLs (do not hydrolyze cefoxitin). * The different shading in the Class D carbapenemases row represents that resistance of OXA-type carbapenemases to 3rd and 4th generation cephalosporins is variable, depending on the carbapenemase variant; OXA-48 and OXA-58 have no intrinsic activity against expanded-spectrum cephalosporins, while OXA-163 and OXA-146 hydrolyze expanded-spectrum cephalosporins [63,108]. Abbreviations: Ceph: cephalosporin; BSBL: broad spectrum β-lactamase; ESBL: extended spectrum β-lactamase; KPC, Klebsiella pneumoniae Carbapenemase; IMP, Imipenemase type carbapenemase; NDM-1, New Delhi metallo-β-lactamase; VIM, Verona integron-encoded metallo-β-lactamase; OXA, oxacillinase.