First generation cephalosporins, including cefazolin, are active against most gram-positive cocci except for enterococci, oxacillin-resistant staphylococci, and penicillin-resistant pneumococci. They are also active against most strains of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae.
The second generation cephalosporins include two subgroups. One subgroup has activity against Haemophilus influenzae and Moraxella catarrhalis. The other subgroup consists of the cephamycins, which are active against many strains of Bacteroides.
Third generation cephalosporins have less activity against most gram-positive organisms than first generation agents but are highly active against Enterobacteriaceae, Neisseria, and H. influenzae. Ceftazidime is also active against Pseudomonas aeruginosa.
The fourth generation cefepime has similar activity as the third generation cephalosporins, including against P. aeruginosa, with the addition of greater activity against enteric gram-negative rods that have an inducible chromosomal beta-lactamase.
The fifth generation cephalosporin ceftaroline has activity against oxacillin-resistant staphylococci, penicillin-resistant pneumococci, and enteric gram-negative rods.
Oral cephalosporins are also divided into different generations and their spectra of activity generally mirror those parenteral agents of the corresponding generation. However, oral third generation drugs are less active against enteric gram-negative bacteria than the parenteral third generation cephalosporins. Second and third generation oral cephalosporins have similar indications, namely otitis media, respiratory tract infections, and urinary tract infections.
Many of the available parenteral cephalosporins have short serum half-lives and require frequent administration. All of the cephalosporins except ceftriaxone require dose modification in the presence of severe renal failure.
All of the cephalosporins achieve therapeutic levels in pleural, pericardial, peritoneal, and synovial fluids, and urine. First and second generation cephalosporins enter into cerebrospinal fluid poorly. Third generation cephalosporins achieve more reliable cerebrospinal fluid levels in patients with meningeal irritation.
CLASSIFICATION OF CEPHALOSPORINS
First generation (cefazolin)
- Subgroup with activity against Haemophilus influenzae (cefuroxime)
- Cephamycin subgroup with activity against Bacteroides spp (cefoxitin and cefotetan)
- Subgroup with broad gram negative activity but poor activity against Pseudomonas aeruginosa (cefotaxime and ceftriaxone)
- Subgroup with broad gram negative activity including good activity against Pseudomonas aeruginosa (ceftazidime)
Fourth generation (cefepime)
Fifth generation (ceftaroline)
Ceftaroline is a fifth generation cephalosporin whose active metabolite has a spectrum of in vitro activity similar to ceftriaxone but with improved gram-positive activity. In particular, ceftaroline has higher affinity for PBP2a in oxacillin-resistant staphylococci, and has activity against MRSA, as well as vancomycin-intermediate Staphylococcus aureus (VISA) and hetero-VISA. In addition, ceftaroline has activity for Streptococcus pneumoniae that is intermediate or resistant to penicillin or ceftriaxone. Ceftaroline is not active for enterococci nor against AmpC-overproducing or ESBL-producing Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, or Bacteroides fragilis. Two randomized, double-blind controlled clinical trials have suggested that ceftaroline is noninferior to vancomycin plus aztreonam for treatment of complicated skin and soft tissue infections including those due to MRSA, and to ceftriaxone for therapy of community-acquired pneumonia. The efficacy of this anti-MRSA cephalosporin is not yet known for hospital-acquired MRSA pneumonia or for bacteremia.
Cephalosporins available for oral use include cephalexin, cefadroxil, cefaclor, cefuroxime axetil, cefprozil, cefixime, cefpodoxime proxetil, ceftibuten, cefdinir, and cefditoren.
Among the first generation cephalosporins available for oral use, cefadroxil has a longer serum half-life than cephalexin and is generally given in a dose of 500 to 1000 mg every 12 hours. The oral cephalosporins are poorly active against penicillin-resistant pneumococci.
The oral second generation cephalosporins, cefaclor, cefuroxime axetil, and cefprozil, have improved activity against H. influenzae compared with the first generation oral cephalosporins and may be useful in treating otitis, sinusitis, and respiratory tract infections.
The oral third generation cephalosporins, cefixime, cefpodoxime proxetil, ceftibuten, cefdinir, and cefditoren, are active against streptococci, H. influenzae (including beta-lactamase producing strains), and M. catarrhalis. They are more active than the other oral cephalosporins against enteric gram-negative bacilli, including E. coli, P. mirabilis, and Klebsiella. However, they have poor activity against most strains of Enterobacter, Acinetobacter, P. aeruginosa, and the anaerobes. Cefixime and ceftibuten have little activity against staphylococci, but cefpodoxime proxetil and cefdinir have more activity. Ceftibuten is also only weakly active against pneumococci. Its spectrum of activity is otherwise similar to those of cefdinir and cefpodoxime.
These antibiotics are relatively stable to many plasmid-mediated beta-lactamases but are much less stable to common chromosomally-mediated cephalosporinases. Although these antibiotics are promoted as oral third generation cephalosporins, they are less active against the enteric gram-negative bacilli than the parenteral third or fourth generation cephalosporins. These antibiotics are recommended as therapy for otitis media, upper and lower respiratory tract infections, and urinary tract infections (cefixime, cefpodoxime, and cefdinir). These indications are shared with the oral second generation cephalosporins, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole. Cefixime and ceftibuten have little or no activity against staphylococci in contrast to some of these other agents.
Clin Infect Dis. 2010;51(6):641.
- Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection.
Clin Infect Dis. 2010;51(12):1395.
- Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia.
Clin Infect Dis. 2012;55 Suppl 3:S173.
- Summary of ceftaroline fosamil clinical trial studies and clinical safety.