Third-generation cephalosporins are used to treat a wide variety of serious infections caused by organisms that are resistant to most other drugs. Strains expressing extended-spectrum β-lactamases, however, are not susceptible. Third-generation cephalosporins should be avoided in treatment of Enterobacter infections—even if the clinical isolate appears susceptible in vitro—because of emergence of resistance. Ceftriaxone and cefotaxime are approved for treatment of meningitis, including meningitis caused by pneumococci, meningococci, H influenzae, and susceptible enteric Gram-negative rods, but not by L monocytogenes. Ceftriaxone and cefotaxime are the most active cephalosporins against penicillinnon-susceptible strains of pneumococci and are recommended for empirical therapy of serious infections that may be caused by these strains. Meningitis caused by strains of pneumococci with penicillin MICs >1 mcg/mL may not respond even to these agents, and addition of vancomycin is recommended. Other potential indications include empirical therapy of sepsis in both the immunocompetent and the immunocompromised patient and treatment of infections for which a cephalosporin is the least toxic drug available.
Cefepime is the only available fourth-generation cephalosporin. It is more resistant to hydrolysis by chromosomal β-lactamases (eg, those produced by Enterobacter). However, like the third-generation compounds, it is hydrolyzed by extended-spectrum β-lactamases. Cefepime has good activity against P aeruginosa, Enterobacteriaceae, methicillin-susceptible S aureus, and S pneumoniae. It is highly active against Haemophilus and Neisseria sp. It penetrates well into cerebrospinal fluid. It is cleared by the kidneys and has a half-life of 2 hours, and its pharmacokinetic properties are very similar to those of ceftazidime. Unlike ceftazidime, however, cefepime has good activity against most penicillin-nonsusceptible strains of streptococci, and it is useful in treatment of Enterobacter infections. The standard dose for cefepime is 1–2 g infused every 12 hours; however, when treating more complicated infections due to P aeruginosa or in the setting of immunocompromise, doses are typically increased to 2 g every 8 hours. Because of its broad-spectrum activity, cefepime is commonly used empirically in patients presenting with febrile neutropenia, in combination with other agents.
Beta-lactam antibiotics with activity against methicillin-resistant staphylococci are currently under development. Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, is the first such drug to be approved for clinical use in the USA. Ceftaroline has increased binding to penicillin-binding protein 2a, which mediates methicillin resistance in staphylococci, resulting in bactericidal activity against these strains. It has some in vitro activity against enterococci and a broad Gram-negative spectrum similar to ceftriaxone. It is not active against AmpC or extended-spectrum β-lactamase-producing organisms. Ceftaroline is currently approved for the treatment of skin and soft tissue infections and community-acquired pneumonia at a dose of 600 mg infused every 12 hours. It has been used off-label to treat complicated infections such as bacteremia, endocarditis, and osteomyelitis, sometimes in combination with other agents and often at an increased dose of 600 mg every 8 hours. The normal half-life is about 2.7 hours; ceftaroline is primarily excreted renally and requires dose adjustment in renal impairment.
Cephalosporins Combined with a-lactamase Inhibitors