The fourth-generation cephalosporins: Antimicrobial activity and spectrum definitions using cefpirome as an example

The antimicrobial activity of cefpirome against routine clinical isolates and those organisms resistant to a “third-generation” cephalosporin was highly consistent within a nation (US.) and among various countries. It demonstrated reasonable activity against ceftazidime-resistant Enterobacteriaceae and excellent activity against staphylococci while maintaining usable potency against P. aeruginosa (MIC₅₀, 4 μg/ml).¹² The association of relative stability to Bush group 1 β-lactamases, lower enzyme affinity, and increased penetration through the bacterial outer membrane appears to be responsible for the higher activity of “fourth-generation” cephalosporins against aerobic Gram-negative bacteria.^{5,8,16,23,25,28} In addition, cefpirome has achieved a more balanced spectrum, with activity against important contemporary Grampositive cocci, a potency comparable to that of a “first-generation cephalosporin.^2,27,30 Its in vitro activity against oxacillin-resistant staphylococci could be explained by a higher affinity for the staphylococcal PBPs, including PBP2a,²⁷ however, the clinical significance of this finding has yet to be demonstrated. “Fourth-generation” compounds such as cefpirome have more limited activity against Gram-negative anaerobic bacilli¹⁵ compared to the “third-generation” compounds.

In vitro studies have shown that cefpirome has potent activity against Enterobacteriaceae and staphylococci strains resistant to the “third-generation” cephalosporin, ceftazidime. Moreover, pharmacokinetics studies in healthy volunteers showed encouraging results allowing for twice daily dosing.²⁴ Further in vitro and in vivo investigations should be performed to determine the role of this and other similar compounds in the treatment of infections caused by these multiresistant bacteria. Combination chemotherapy with aminoglycosides or glycopeptides or metronidazole maybe required to eradicate some emerging clinical pathogens.