Penicillins and β-Lactamase Inhibitors

After almost a century since the initial discovery of penicillin G, penicillins remain a clinically valuable class of β-lactams today. They trigger cell death through binding with penicillin-binding proteins (PBPs) and consequent inhibition of bacterial cell wall synthesis. Penicillins are divided into five classes on the basis of antibacterial activity, with considerable overlap among the classes: natural penicillins, penicillinase-resistant penicillins, aminopenicillins, carboxypenicillins, and ureidopenicillins. The carboxypenicillins and ureidopenicillins are also referred to as antipseudomonal penicillins. Resistance to penicillins occurs through destruction of the antibiotic by β-lactamase, failure of antibiotic to penetrate the outer membrane of gram-negative bacteria to reach PBP targets, efflux of drug across the outer membrane of gram-negative bacteria, and low-affinity binding of antibiotic to target PBPs. The pharmacodynamic parameter that predicts efficacy of penicillins is the time of free plasma drug concentration exceeding the minimal inhibitory concentration (fT > MIC). Penicillins are primarily cleared renally by glomerular filtration and renal tubular secretion. The most important adverse effects of the penicillins are hypersensitivity reactions, but the actual incidence of severe reactions is low. To overcome β-lactamase-mediated resistance, various β-lactamase inhibitors have been developed, and newer ones are being actively developed to address emergent, potent β-lactamases, such as carbapenemases. They all bind to the active site of serine β-lactamases and prevent hydrolysis of partner β-lactams. Combining with β-lactamase inhibitors generally expands the spectrum of β-lactams to include methicillin-susceptible staphylococci, gram-negative pathogens, and intestinal anaerobic pathogens, although the specific spectrum of activity differs for each β-lactam-β-lactamase combination.