Pathophysiologic basis for the use of third-generation cephalosporins.

After 10 years of use, the third-generation cephalosporins remain excellent antibiotics. They have superior activity against selected streptococcal species compared with other cephalosporins, and superior activity against Haemophilus, Neisseria, Branhamella, and other less common oral gram-negative aerobic species. Despite a very broad spectrum of activity, the third-generation cephalosporins, like all other cephalosporins, have only poor activity against enterococci, Listeria, Corynebacterium jekeium, and methicillin-resistant staphylococci. Over the past 10 years, the activity of the third-generation cephalosporins against Escherichia coli, Klebsiella, Proteus, Providencia, Serratia, Haemophilus, and Neisseria has remained excellent. Equally as important, though perhaps less well recognized, is the activity of some of these agents against mouth anaerobic species and the anaerobic Bacteroides and Clostridium spp. of the pelvic area. At present, there are two main threats to the continued use of the third-generation cephalosporins. These are the increasing number of infections due to Enterobacter spp., which constitutively produce large amounts of a beta-lactamase that hydrolyzes cephalosporins, and the recent appearance of Klebsiella spp. in many parts of the world that possess new plasmid-mediated beta-lactamases that destroy cefotaxime, ceftazidime, and related third-generation parenteral cephalosporins. Correlation of pharmacologic properties with in vitro activity provides information as to reasonable dosage regimens for the third-generation cephalosporins. For most serious infections cefotaxime, ceftizoxime, and ceftazidime should be given three times a day provided that the patient has relatively normal renal function. Ceftriaxone can be administered once daily in less severe infections. The use of lower doses or less frequent dosing with cefotaxime, ceftizoxime, or ceftazidime is recommended in aged patients whose renal function is impaired. The unique interaction of cefotaxime with its active metabolite, desacetylcefotaxime, allows cefotaxime to be administered less frequently than three times a day in selected anaerobic infections. Correlation of the antibacterial activity and pharmacology of cephalosporins will help us to tailor their use more appropriately, so that the third-generation cephalosporins will remain useful antimicrobial agents for a further decade.