Compared with second-generation agents, these drugs have expanded Gram-negative coverage, and some are able to cross the blood-brain barrier. Third-generation drugs may be active against Citrobacter, S marcescens, and Providencia. They are also effective against β-lactamase-producing strains of Haemophilus and Neisseria. Ceftazidime is the only agent with useful activity against P aeruginosa. Like the second-generation drugs, third-generation cephalosporins are hydrolyzed by constitutively produced AmpC β-lactamase, and they are not reliably active against Enterobacter species. Serratia, Providencia, Acinetobacter, and Citrobacter also produce a chromosomally encoded cephalosporinase that, when constitutively expressed, can confer resistance to third-generation cephalosporins. Cefixime, cefdinir, ceftibuten, and cefpodoxime proxetil are oral agents possessing similar activity except that cefixime and ceftibuten are much less active against pneumococci and have poor activity against S aureus.
Intravenous infusion of 1 g of a parenteral cephalosporin produces serum levels of 60–140 mcg/mL. Third-generation cephalosporins penetrate body fluids and tissues well and intravenous cephalosporins achieve levels in the cerebrospinal fluid sufficient to inhibit most susceptible pathogens.
The half-lives of these drugs and the necessary dosing intervals vary greatly: ceftriaxone (half-life 7–8 hours) can be injected once every 24 hours at a dosage of 15–50 mg/kg/d. A single daily 1-g dose is sufficient for most serious infections, with 2 g every 12 hours recommended for treatment of meningitis and 2 g every 24 hours recommended for endocarditis. The remaining drugs in the group (half-life 1–1.7 hours) can be infused every 6–8 hours in dosages between 2 and 12 g/d, depending on the severity of infection. Cefixime can be given orally (200 mg twice daily or 400 mg once daily) for urinary tract infections. Due to increasing resistance, cefixime is no longer recommended for the treatment of uncomplicated gonococcal urethritis and cervicitis. Intramuscular ceftriaxone in combination with azithromycin is the regimen of choice for treating most gonococcal infections. The adult dose for cefpodoxime proxetil or cefditoren pivoxil is 200–400 mg twice daily; for ceftibuten, 400 mg once daily; and for cefdinir, 300 mg/12 h. Ceftriaxone excretion is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. The other third-generation cephalosporins are excreted by the kidney and therefore require dosage adjustment in renal insufficiency.