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 and cefotaxime 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 has also been used most 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 the clinical microbiology laboratory.
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 equal to 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 little 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 is 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.
The half-lives of these medications are variable, resulting in differing dosage needs. Ceftriaxone is eliminated primarily by biliary excretion, and no dosage adjustment is required in kidney disease. The other medications are eliminated primarily by the kidney and thus require dosage adjustment 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 rods. In older patients with meningitis, third-generation cephalosporins should be combined with ampicillin or trimethoprim-sulfamethoxazole until L monocytogenes has been excluded. 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 in the febrile neutropenic patient since these medications are active against Pseudomonas and most enteric Enterobacteriaceae that translocate into the blood of patients with chemotherapy-induced enteritis. 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. While cefepime has an extended spectrum of activity compared with third-generation agents, a meta-analysis revealed increased all-cause mortality with this agent when compared with other beta-lactams. Additional analyses have refuted this finding, and cefepime appears no different than any other beta-lactam with respect to mortality risk. 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 if gram-negative pathogens are coinfecting.
Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are the most active third-generation oral agents against pneumococci and S aureus. Cefixime is available in an oral suspension and 400-mg tablets. However, as a result of increased resistance, cefixime is not reliable in the treatment of gonorrhea; when cefixime is used (rather than ceftriaxone), proof of cure is necessary.