Most of these medications are active against staphylococci but less so than first-generation cephalosporins. Ceftazidime, however, has notably weak activity against S aureus and pneumococci. While inactive against enterococci, most third- and fourth-generation cephalosporins inhibit most streptococci (ceftazidime is an exception to this rule). Ceftriaxone, cefotaxime, and ceftaroline offer the most reliable antipneumococcal coverage. A major advantage of third-, fourth-, and fifth generation cephalosporins over the first and second generations is their expanded gram-negative coverage. In addition to organisms inhibited by other cephalosporins, they are more active against Serratia marcescens, Providencia, Haemophilus, and Neisseria, including beta-lactamase–producing strains. Ceftazidime is unique among all third-generation agents because it is active against P aeruginosa. Nonaeruginosa strains of Pseudomonas are often resistant to third-generation cephalosporins, and Listeria is uniformly resistant. Activity against B fragilis is variable. In contrast to the third-generation agents, cefepime—the only fourth-generation cephalosporin—is more active against Enterobacter and Citrobacter, has activity comparable to that of ceftazidime against P aeruginosa, and has gram-positive activity similar to that of ceftriaxone. Cefepime has demonstrated equal efficacy to carbapenems for the treatment of Enterobacter, potentially sparing these more broad-spectrum agents. Among the cephalosporins, cefepime is frequently in the treatment of multidrug-resistant P aeruginosa, specifically using an extended-infusion. While cefepime is often active against ESBL-producing organisms, it is clinically less reliable when compared to carbapenems. The extended infusion takes advantage of the time-dependent pharmacodynamics of cefepime, resulting in a useful option, even for those isolates considered to be “resistant” by in vitro microbiology testing methods. Cefiderocol is a siderophore cephalosporin sharing structural similarities with both cefepime and ceftazidime, but with a novel means of accessing the site of action. Cefiderocol uses the bacterial iron transport system to enter the bacterial cell, allowing it to bypass resistance mechanisms, such as porin alterations. Cefiderocol is primarily active against aerobic gram-negative bacteria, including Pseudomonas, and retains activity against beta-lactamases, such as AmpC, ESBL, and KPC-producing Enterobacteriaceae.
Cefpodoxime proxetil, cefdinir, cefditoren pivoxil, cefixime, and ceftibuten (the only oral agents in this group) are more active than cefuroxime axetil against gram-negative pathogens. However, none of these oral agents are as active as the parenteral third-generation cephalosporins against these pathogens. All third- and fourth-generation cephalosporins are uniformly active against S pyogenes (group A Streptococcus). Cefpodoxime proxetil, cefditoren pivoxil, and cefdinir are active against methicillin-susceptible S aureus, whereas ceftibuten has limited activity (none are active against methicillin-resistant strains). Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are active against penicillin-susceptible strains of S pneumoniae (the pneumococcus), but ceftibuten has marginal activity. None of the oral cephalosporins are reliable against intermediately susceptible or penicillin-resistant S pneumoniae. Similar to other members of this class, these medications are ineffective against enterococci and Listeria monocytogenes. The one available fifth-generation cephalosporin ceftaroline is unique in that it represents the only beta-lactam available in the United States with in vitro activity against methicillin-resistant S aureus. (Ceftobiprole has activity against methicillin-resistant S aureus but is only available commercially outside of the United States.) Unlike other beta-lactams, ceftaroline binds PBP2a, a penicillin binding protein encoded by the mecA gene in methicillin-resistant S aureus. The gram-negative spectrum of activity of ceftobiprole approximates that of ceftriaxone; thus, it is inactive against P aeruginosa, Acinetobacter species (spp), and B fragilis.
Pharmacokinetics & Administration
The intravenous third- and fourth-generation agents distribute into extracellular fluid and reach levels in the cerebrospinal fluid exceeding those needed to inhibit susceptible pathogens, particularly in the presence of inflamed meninges. At the present time, the cerebrospinal fluid penetration of ceftaroline and cefiderocol are unknown; however, successful use of ceftaroline in the treatment of complicated methicillin-resistant S aureus central nervous system infections, such as meningitis, has been reported. Cefiderocol is primarily excreted in the urine as unchanged drug and approved for the treatment of complicated urinary tract infections at a dose of 2 g every 8 hours as a 3-hour extended intravenous infusion.
The half-lives of the third-, fourth-, and fifth-generation agents vary, resulting in differing dosage frequency. Ceftriaxone has the longest half-life and differs from the others in that it is eliminated primarily by biliary excretion; no dosage adjustment is required in kidney disease.
Because of their penetration into the cerebrospinal fluid and potent in vitro activity, intravenous third-generation cephalosporins are effective in the treatment of meningitis due to susceptible pneumococci, meningococci, H influenzae, and certain enteric gram-negative bacilli. In older patients with meningitis, third-generation cephalosporins empirically should be combined with ampicillin or trimethoprim-sulfamethoxazole to cover L monocytogenes. Ceftazidime has been used to treat meningitis due to Pseudomonas. The dosage for meningitis should be at the upper limits of the recommended range, because cerebrospinal fluid levels of these medications are only 10–20% of serum levels. Ceftazidime or cefepime is frequently administered empirically for febrile neutropenia due to their activity against Pseudomonas and most enteric Enterobacteriaceae. Ceftriaxone is indicated for gonorrhea, chancroid, and more serious forms of Lyme disease. Because of its long half-life and once-daily dosing requirement, ceftriaxone is widely used in the outpatient parenteral therapy of infections due to susceptible organisms.
Cefepime is useful for third-generation cephalosporin–resistant isolates such as Enterobacter and Citrobacter. Considering its spectrum of activity, including methicillin-resistant S aureus, ceftaroline is useful in the treatment of skin and soft tissue infections due to this pathogen, particularly with coinfecting gram-negative pathogens. Cefiderocol is the only available cephalosporin without a coformulated beta-lactamase inhibitor that retains activity against resistant gram-negative organisms, including Pseudomonas, Acinetobacter baumannii, Stenotrophomonas maltophilia, and carbapenem-resistant Enterobacteriaceae (CRE).
Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are the most active oral third-generation agents against pneumococci and S aureus. Cefixime is available in an oral suspension and 400-mg tablets. While cefixime has been used in the treatment of gonorrhea (rather than ceftriaxone), proof of cure is necessary.