Cephalosporins

Introduction to Cephalosporins

The cephalosporins are probably the most confusing group of antibiotics. For convenience, they have been grouped into “generations” that largely correlate with their spectrum of activity, with some notable exceptions. Although there are many different individual agents, the good news is that most hospitals use only a few of them, so, in practice, learning your institution’s cephalosporins of choice is easy. In general, it is best to learn the characteristics of each generation and then learn the quirks about the individual agents.  

Cephalosporins have several elements in common:

• All have some cross-allergenicity with penicillins, though there are differences among generations. Estimates about the likelihood  of cross-reactivity between penicillin and cephalosporin allergies differ. It is likely very low,  below the oft-quoted 10%. A reasonable estimate is no more than 3% to 5%, though some publications support even lower numbers, particularly for later-generation agents. However, using any cephalosporin in a patient with a penicillin allergy is a matter of balancing risks and benefits. Assess the validity of the patient’s allergy through interview and consider the level of risk associated with cephalosporin ad-ministration. Be skeptical of nausea, but be sure to take hives and any signs of anaphylaxis very seriously! Use alternative classes of antibiotics when practical.

• The cephalosporins are generally more resistant to beta-lactamases than penicillins are.  Beta-lactamases that are active against penicillins but inactive against cephalosporins are called  penicillinases. Beta-lactamases that in-activate cephalosporins (cephalosporinases) also bexist and are increasing in prevalence.

• None of the currently available cephalosporins have useful activity against enterococci.

First-Generation Cephalosporins

Agents: cefazolin, cephalexin, cefadroxil, cephalothin

First-generation cephalosporins are the most commonly used class of antibiotics in the hospital.  Why? They are used immediately prior to surgery to prevent surgical site infections. Their spectrum of activity, inexpensive cost, and low incidence of adverse effects make them ideal for this purpose.

Spectrum

Good: MSSA, streptococci

Moderate: some enteric GNRs

Poor: enterococci, anaerobes, MRSA, Pseudomonas

Adverse Effects

Similar to those of other beta-lactams.

Important Facts

• First-generation cephalosporins are good alternatives to antistaphylococcal penicillins. They cause less phlebitis and are infused less frequently. Unlike antistaphylococcal penicillins,  however, they do not cross the blood-brain barrier and should not be used in central nervous system (CNS) infections.

• Cephalexin and cefadroxil are available orally;  the others are parenteral.

What They’re Good For

Skin and soft-tissue infections, surgical prophylaxis, staphylococcal endocarditis (MSSA).

Don’t Forget!

Surgical prophylaxis is the most common indica-tion for first-generation cephalosporins in the hospital. Be sure to limit the duration of therapy for this use; administering more than one dose of antibiotics should be uncommon, and giving more than 24 hours of antibiotics is rarely justified. Such use does not lower infection rates, but it can select for more resistant organisms later in the hospital stay.

Second-Generation Cephalosporins

Agents: cefuroxime, cefoxitin, cefotetan,  cefprozil, loracarbef, cefmetazole, cefonicid, cefamandole, cefaclor

 Compared with first-generation cephalosporins,  second-generation agents have better Gram-negative activity and somewhat weaker Gram-positive activity, though they are still used for these organisms. They are more stable against Gram-negative beta-lactamases and are particularly active against Haemophilus influenzae and Neisseria gonorrheae. Though the second-generation agents are the most numerous cephalosporins, they are probably the least utilized in U.S. hospitals.

Spectrum

Good: some enteric GNRs, Haemophilus, Neisseria

Moderate: streptococci, staphylococci, anaerobes

(only cefotetan, cefoxitin, cefmetazole)

Poor : enterococci, MRSA, Pseudomonas

Adverse Effects

Similar to those of other beta-lactams. Cephalosporins with the N-methylthiotetrazole (MTT) side chain—cefamandole, cefmetazole, and cefotetan—can inhibit vitamin K production and prolong bleeding. These MTT cephalosporins can also cause a disulfuram-like reaction when co-administered with ethanol. While most people in the hospital do   not have access to alcoholic beverages while being treated for infections, outpatients need to be counseled on this interaction. The interaction is a common question on board exams.

Important Facts

• Cefoxitin, cefotetan, and cefmetazole are cephamycins. They are grouped with the second-generation cephalosporins because they have  similar activity, with one important exception: anaerobes. Cephamycins have activity against  many anaerobes in the GI tract, and cefoxitin and cefotetan are often used for surgical prophylaxis in abdominal surgery.

• Loracarbef is technically a carbacepham. You should immediately forget this to allow room for more important facts.

• Cefaclor, cefprozil, and loracarbef are available only orally. Cefuroxime is available in both IV and oral formulations, and the others are IV only.

• Like first-generation cephalosporins, second-generation agents do not cross the blood-brain barrier well enough to be useful to treat CNS infections.

What They’re Good For

Upper respiratory tract infections, community-acquired pneumonia, gonorrhea, surgical prophylaxis (cefotetan, cefoxitin, cefuroxime).

Don’t Forget!

The cephamycins have good intrinsic anaerobic activity, but resistance to them is increasing in Bacteroides fragilis group infections. When using them for surgical prophylaxis, limit the duration of antibiotic exposure after surgery. If an infection does develop, use alternative agents such as beta-lactamase inhibitor combinations or another Gram-negative agent with metronidazole.

Third-Generation Cephalosporins

Agents: ceftriaxone, cefotaxime, ceftazidime,  cefdinir, cefpodoxime, cefixime, ceftibuten

Third-generation cephalosporins have greater Gram-negative activity than the first- and second-generation drugs. They also have good streptococcal activity, but generally lesser staphylococcal activity than previous generations of cephalosporins. These are broad-spectrum agents that have many different uses.

Spectrum

Good: streptococci, enteric GNRs,  Pseudomonas  (ceftazidime only)

Moderate: MSSA (except ceftazidime, which is poor)

Poor : enterococci,  Pseudomonas (except ceftazidime), anaerobes, MRSA

Adverse Effects

Similar to those of other beta-lactams. Third-generation cephalosporins have been shown to be one of the classes of antibiotics with the strongest association with  Clostridium difficile–associated diarrhea. Cefpodoxime has the MTT side chain that can inhibit vitamin K production.

Important Facts

• Ceftazidime is the exception to the spectrum of activity rule for third-generation agents. Un-like the others, it is antipseudomonal and lacks clinically useful activity against Gram-positive organisms.

• Ceftriaxone, cefotaxime, and ceftazidime cross the blood-brain barrier effectively and are useful for the treatment of CNS infections. How-ever, their differences in spectrum lead clinicians to use them for different types of infections. Ceftazidime would be a poor choice for community-acquired meningitis, in which Streptococcus pneumoniae predominates.

• Third-generation cephalosporins are notorious for inducing resistance among GNRs. Though they can be useful in nosocomial infections, too much broad-spectrum utilization can result in harder-to-treat organisms.

• Ceftriaxone has the characteristic of having dual modes of elimination via both renal and biliary excretion. It does not need to be adjusted for renal dysfunction.

• Ceftriaxone has two problems that make its use in neonates problematic: it interacts with calcium-containing medications to form crystals that can precipitate in the lungs and kidneys, which has led to fatalities, and it can also lead to biliary sludging with resultant hyperbilirubinemia. Cefotaxime is a safer drug for these young patients.

What They’re Good For

Lower respiratory tract infections, pyelonephritis,  nosocomial infections (ceftazidime), Lyme disease  (ceftriaxone), meningitis, skin and soft-tissue infections, febrile neutropenia (ceftazidime).

Don’t Forget!

Ceftriaxone is a once-daily drug for almost all indi-cations except meningitis. Make sure your meningitis patients receive the full 2 gram IV q12h dose and also use vancomycin and ampicillin (if indicated).

Fourth-Generation Cephalosporins

Agent: cefepime

There is only one fourth-generation cephalosporin,  cefepime. Cefepime is the broadest-spectrum cephalosporin, with activity against both Gram-negative organisms, including  Pseudomonas, and Gram-positive organisms. One way to remember its spectrum is to think that cefazolin  + ceftazidime  = cefepime.

Spectrum

Good: MSSA, streptococci,  Pseudomonas, enteric

GNRs

Moderate: Acinetobacter

Poor : enterococci, anaerobes, MRSA

Adverse Effects

Similar to those of other beta-lactams.

Important Facts

• Cefepime is a broad-spectrum agent. It is a good empiric choice for many nosocomial  infections, but overkill for most community-acquired infections. Be sure to de-escalate therapy if possible when you treat empirically with cefepime.

• For monotherapy of febrile neutropenia, cefepime is a better choice than ceftazidime be-cause 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.

What It’s Good For

Febrile neutropenia, nosocomial pneumonia,  post-neurosurgical 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,    is overkill for most community-acquired sources of these infections.

Fifth-Generation Cephalosporins

Agents: ceftaroline, ceftobiprole

Two new cephalosporins have recently been developed with unique characteristics. We are anticipating that they will be marketed as “fifth-generation”  cephalosporins, although there is no consensus on the issue yet. What makes these agents unique is their activity against MRSA. Their structures have  been engineered to bind to the penicillin-binding protein 2a of MRSA that has low affinity for other beta-lactams. Unlike other cephalosporins, these agents also have modest activity against Enterococcus faecalis (but not  Enterococcus faecium). They lose some of the Gram-negative potency of cefepime; their Gram-negative activity is closer to that of ceftriaxone. In an era of high MRSA prevalence, these agents offer intriguing possibilities for therapy, but because they are so new their role is not yet defined.

Spectrum

Good: MSSA, MRSA, streptococci, enteric GNRs

Moderate: Acinetobacter, Enterococcus faecalis

Poor : Pseudomonas aeruginosa, Enterococcus faecium, anaerobes

Adverse Effects

Information available to date from clinical trials suggests adverse effects of these agents are similar to those of other beta-lactams.

Important Facts

• As is typical for new antimicrobials coming to market, the initial indications for these agents are “low-hanging fruit”: skin and soft tissue infections and community-acquired pneumonia. These are indications for which there are al-ready a great many agents available. The challenge will be to determine what the role of these drugs is for hospital-acquired pneumonia and other severe diseases often caused by drug-resistant pathogens.

What They’re Good For

Ceftaroline is approved (in the United States) for

treatment of complicated skin and soft tissue infections and community-acquired pneumonia. Ceftobiprole is approved for treatment of complicated skin and soft tissue infections in Canada but has not been approved in the United States at this time.

Don’t Forget!

If you want to think about these drugs as fifth-generation agents, just don’t forget that their Gram-negative activity is less compared to the fourth generation, especially as regards  Pseudomonas aeruginosa.

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.