Important Facts
Cefepime is a broad-spectrum agent. It is a good empiric choice for many nosocomial infections, but it is overkill for most community-acquired infections. Be sure to deescalate therapy if possible when you treat empirically with cefepime.
For monotherapy of febrile neutropenia, cefepime is a better choice than ceftazidime because of its better Gram-positive activity. It may also induce less resistance in GNRs than third-generation cephalosporins, but it is still not a good drug to overuse.
Cefepime briefly had a bad reputation after a meta-analysis showed increased mortality with its use compared with other drugs. Many clinicians were skeptical, however, and a more thorough FDA analysis exonerated cefepime.
Neurotoxicity with cefepime can occur and may manifest as nonconvulsive status epilepticus. It can occur at any dose, but dose adjustment of the drug for patients with renal dysfunction is important.
What It’s Good For
Febrile neutropenia, nosocomial pneumonia, postneurosurgical meningitis, other nosocomial infections.
Don’t Forget!
Cefepime is used primarily for nosocomial infections. Although it is indicated for infections of the urinary tract and lower respiratory tract, it is overkill for most community-acquired sources of these infections.
Anti-MRSA Cephalosporins
Agent: ceftaroline
Ceftaroline is a cephalosporin that has unique characteristics that defy the “generational” label. The CLSI has designated it an “anti-MRSA cephalosporin,” which we’re going with since it highlights the most important characteristic of the drug. What makes this agent unique is activity against MRSA. Its structure has been engineered to bind to the penicillin-binding protein 2a of MRSA that has low affinity for other beta-lactams. Unlike other cephalosporins, ceftaroline also has modest activity against E. faecalis (but not E. faecium). It lost some of the Gram-negative potency of cefepime and has Gram-negative activity similar to that of ceftriaxone. In an era of high MRSA prevalence, ceftaroline offers an intriguing possibility for therapy, but because it is fairly new its role is not yet defined. Another agent with similar characteristics exists (ceftobiprole), but it was removed from the market in the few countries in which it was approved after U.S. and E.U. regulators did not approve it.
Mechanism of Action
All beta-lactams inhibit cross-linking of peptidoglycan in the cell wall, leading to autolysis and cell death. Unlike other beta-lactams, ceftaroline can bind to penicillin-binding protein 2a, a type that is expressed by MRSA. This characteristic is responsible for its anti-MRSA activity.
Spectrum
Good: MSSA, MRSA, streptococci, enteric GNRs
Moderate: E. faecalis
Poor: P. aeruginosa, E. faecium, Acinetobacter, anaerobes
Adverse Effects
Information available to date from clinical trials suggests adverse effects of ceftaroline are similar to those of other beta-lactams.
Important Facts
As is typical for new antimicrobials coming to market, the initial indications for ceftaroline are “low-hanging fruit”: skin and skin structure infections and community-acquired pneumonia. These are indications for which there are already a great many agents available, though ceftraroline outperformed ceftriaxone in community-acquired pneumonia in two of the three studies. The challenge will be to determine what the role of ceftaroline is for hospital-acquired pneumonia and other severe diseases often caused by drug-resistant pathogens. Ceftaroline has been described in case series and retrospective studies to successfully treat bloodstream infections, endocarditis, meningitis, osteomyelitis, and hospital-acquired pneumonia.
What it’s Good For
Ceftaroline is approved (in the United States) for treatment of complicated skin and soft tissue infections and community-acquired pneumonia. There are less rigorous data for other uses.
Don’t Forget!
Some references are describing ceftaroline as a fifth-generation cephalosporin (including us just one edition ago). If you choose to categorize it this way, just don’t forget that its Gram-negative activity is less compared to the fourth generation, especially as regards P. aeruginosa.
Cephalosporin/Beta-Lactamase Inhibitor
Combinations
Agents: ceftazidime/avibactam, ceftolozane/tazobactam
Carbapenems, the subject of the next section, have been drugs of choice for some of our most resistant GNRs for many years, so it was no surprise when resistance to them began to emerge. Carbapenem resistance is mostly seen in three key organisms that commonly cause infection: Klebsiella pneumoniae, P. aeruginosa, and A. baumannii. Avibactam is a new type of beta-lactamase inhibitor with a mechanism of action that is different from other beta-lactamase inhibitors and that works against many betalactamases produced by K. pneumoniae and P. aeruginosa. It restores the activity of ceftazidime against many of these organisms. Ceftolozane is a third-generation cephalosporin that evades many resistance mechanisms of
P. aeruginosa, and tazobactam is given with it to protect it from some betalactamases. Neither of the agents have good activity against Acinetobacter. Note the differences in the spectrum of these agents since they dictate their uses in different situations.
Mechanism of Action
All beta-lactams inhibit cross-linking of peptidoglycan in the cell wall, leading to autolysis and cell death. Tazobactam is a beta-lactamase inhibitor that structurally resembles beta-lactams and binds to many beta-lactamases, rendering them unable to inactivate the coadministered beta-lactam. Avibactam does not resemble a beta-lactam, but it also binds betalactamases and renders them inert.
Spectrum
Good: Pseudomonas, enteric GNRs (ceftazidime/avibactam > ceftolozane/tazobactam)
Moderate: some streptococci (ceftolozane/tazobactam)
Poor: most anaerobes, MRSA, MSSA, Acinetobacter
Adverse Effects
Similar to those of other beta-lactams.