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Brian J. Werth

, PharmD, University of Washington School of Pharmacy

Last full review/revision May 2020| Content last modified May 2020

Cephalosporins are bactericidal beta-lactamantibiotics. They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell synthesis. There are 5 generations of cephalosporins (see table Cephalosporins).




1st Generation









2nd Generation










Parenteral or oral

3rd Generation













Ceftazidime plus avibactam






4th Generation



5th Generation



Ceftobiprole (not available in the US)


Novel cephalosporins



Ceftolozane plus tazobactam


* Also classified as a cephamycin.


Cephalosporins penetrate well into most body fluids and the extracellular fluid of most tissues, especially when inflammation (which enhances diffusion) is present. However, the only cephalosporins that reach cerebrospinal fluid levels high enough to treat meningitis are

All cephalosporins penetrate poorly into intracellular fluid and the vitreous humor.

Most cephalosporins are excreted primarily in urine, so their doses must be adjusted in patients with renal insufficiency. Cefoperazone and ceftriaxone, which have significant biliary excretion, do not require such dose adjustment.

Indications for Cephalosporins

Cephalosporins are bactericidal for most of the following:

Cephalosporins are classified in generations (see table Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins). The 1st-generation drugs are effective mainly against gram-positive organisms. Higher generations generally have expanded spectra against aerobic gram-negative bacilli. The 5th-generation cephalosporins ceftaroline and ceftobiprole are active against methicillin-resistant Staphylococcus aureus. Cephalosporins have the following limitations:

First-generation cephalosporins

These drugs have excellent activity against

  • Gram-positive cocci

Oral 1st-generation cephalosporins are commonly used for uncomplicated skin and soft-tissue infections, which are usually due to staphylococci and streptococci.

Parenteral cefazolin is frequently used for endocarditis due to methicillin-sensitive S. aureus and for prophylaxis before cardiothoracic, orthopedic, abdominal, and pelvic surgery.

Second-generation cephalosporins and cephamycins

Second-generation cephalosporins are active against

  • Gram-positive cocci
  • Certain gram-negative bacilli

Cephamycins are drugs that were originally produced by Streptomyces but are now synthetic. They are typically classed with 2nd-generation cephalosporins. Cephamycins are more active against anaerobes, such as

These drugs may be slightly less active against gram-positive cocci than 1st-generation cephalosporins. Second-generation cephalosporins and cephamycins are often used for polymicrobial infections that include gram-negative bacilli and gram-positive cocci. Because cephamycins are active against Bacteroides species, they can be used when anaerobes are suspected (eg, in intra-abdominal sepsis, decubitus ulcers, or diabetic foot infections). However, in some medical centers, these bacilli are no longer reliably susceptible to cephamycins.

Third-generation cephalosporins

These drugs are active against

Most 3rd-generation cephalosporins, including ceftriaxone and cefotaxime, are also active against some gram-positive species, especially streptococci including some strains with reduced penicillin susceptibility. Oral cefixime and ceftibuten have little activity against S. aureus and, if used for skin and soft-tissue infections, should be restricted to uncomplicated infections due to streptococci.

Ceftazidime is active against Pseudomonas aeruginosa but has no appreciable gram-positive activity. Adding avibactam to ceftazidime increases its spectrum to include Enterobacteriaceae that produce AmpC, ESBL, or Klebsiella pneumoniae carbapenemase (KPC).

These cephalosporins have many clinical uses, as does the 4th-generation cephalosporin (see table Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins).

Fourth-generation cephalosporins

The 4th-generation cephalosporin cefepime has activity against

  • Gram-positive cocci (similar to cefotaxime)
  • Gram-negative bacilli (enhanced activity), including P. aeruginosa (similar to ceftazidime), and some AmpC beta-lactamase–producing Enterobacteriaceae, such as Enterobacter species

Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins




3rd- and 4th-generation cephalosporins

Polymicrobial infections involving gram-negative bacilli and gram-positive cocci (eg, intra-abdominal sepsis, decubitus ulcers, diabetic foot infections)

When necessary, used with other drugs to cover anaerobes or enterococci

Ceftriaxone and some other 3rd-generation drugs

Community-acquired bacterial pneumonia

Used with a macrolide to cover atypical pathogens (mycoplasmas, Chlamydophila species, Legionella species)



Acute meningitis suspected to be due to Streptococcus pneumoniae, Haemophilus influenzae, or Neisseria meningitidis

Used with ampicillin to cover Listeria monocytogenes and with vancomycin to cover S. pneumoniae with reduced penicillin sensitivity (pending minimum inhibitory concentration results*)

Cefpodoxime (oral)

Uncomplicated skin and soft-tissue infections due to staphylococci or streptococci

Not used if methicillin-resistant Staphylococcus aureus is suspected


Empiric therapy for postneurosurgical meningitis to cover Pseudomonas aeruginosa

Used with vancomycin to cover methicillin-resistant S. aureus

Ceftazidime plus avibactam

Definitive therapy for ESBL-, AmpC-, or KPC-producing Enterobacteriaceae


Endocarditis caused by HACEK organisms

Endocarditis due to penicillin-sensitive streptococci

Lyme disease with neurologic complications (except isolated Bell palsy), carditis, or arthritis

Uncomplicated gonococcal infections, chancroid, or both

Single IM dose plus a single oral dose of azithromycin

* Pneumococcal strains that are resistant to ceftriaxone and cefotaxime have been reported, and guidelines suggest that if cerebrospinal fluid strains have minimum inhibitory concentrations of ≥ 1.0 mcg/mL, they should be considered nonsusceptible to 3rd-generation cephalosporins.

ESBL = extended-spectrum beta-lactamase; HACEK =Haemophilus species, Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae; KPC = Klebsiella pneumoniae carbapenemase.

Fifth-generation cephalosporins

The 5th-generation cephalosporins ceftaroline and ceftobiprole are active against

  • Methicillin-resistant S. aureus (MRSA)
  • Penicillin-resistant streptococci
  • Ampicillin-susceptible and beta-lactamase–producing Enterococcus faecalis

Their activity against other gram-positive cocci and gram-negative bacilli is similar to that of 3rd-generation cephalosporins. The 5th-generation cephalosporins are not active against Pseudomonas species.

Contraindications to Cephalosporins

Cephalosporins are contraindicated in patients with a history of major hypersensitivity to other cephalosporins. Cross-reactivity with penicillins and other classes of beta-lactams including other cephalosporins is less common than previously thought, especially among patients who have had mild (nonanaphylactic) reactions to penicillins. Furthermore, cross-sensitivity among beta-lactams can often be predicted on the basis of specific chemical and structural features. However, patients who have one antibiotic allergy are somewhat more likely to react to another antibiotic, so cephalosporins should be given cautiously to patients who have had a significant allergic reaction to other beta-lactams (1, 2, 3).

Ceftriaxone is contraindicated as follows:

  • Ceftriaxone IV must not be coadministered with calcium-containing IV solutions (including continuous calcium-containing infusions such as parenteral nutrition) in neonates ≤ 28 days because precipitation of ceftriaxone-calcium salt is a risk. Fatal reactions with ceftriaxone-calcium precipitates in the lungs and kidneys of neonates have been reported. In some cases, different infusion lines were used, and ceftriaxone and calcium-containing solutions were given at different times. To date, no intravascular or pulmonary precipitates have been reported in patients other than neonates who are treated with ceftriaxone and calcium-containing IV solutions. However, because an interaction between ceftriaxone and IV calcium-containing solutions is theoretically possible in patients other than neonates, ceftriaxone and calcium-containing solutions should not be mixed or given within 48 hours of each other (based on 5 half-lives of ceftriaxone)—even via different infusion lines at different sites—to any patient regardless of age. No data on potential interaction between ceftriaxone and oral calcium-containing products or on interaction between IM ceftriaxone and calcium-containing products (IV or oral) are available.
  • Ceftriaxone should not be given to hyperbilirubinemic and preterm neonates because, in vitro, ceftriaxone can displace bilirubin from serum albumin, potentially triggering kernicterus.

Contraindications references

  • 1. Chaudhry SB, Veve MP, Wagner JL: Cephalosporins: A focus on side chains and β-lactam cross-reactivity. Pharmacy (Basel) 7(3):103, 2019. doi: 10.3390/pharmacy7030103.
  • 2. Collins CD, Scheidel C, Anam K, et al: Impact of an antibiotic side chain-based cross-reactivity chart combined with enhanced allergy assessment processes for surgical prophylaxis antimicrobials in patients with beta-lactam allergies. Clin Infect Dis pii:ciaa232, 2020. doi: 10.1093/cid/ciaa232.
  • 3. DePestel DD, Benninger MS, Danziger L, et al: Cephalosporin use in treatment of patients with penicillin allergies. J Am Pharm Assoc (2003) 48(4):530–540, 2008. doi: 10.1331/JAPhA.2008.07006.

Use During Pregnancy and Breastfeeding

Cephalosporins are widely considered to be safe for use during pregnancy. No studies have shown risk to human fetuses, but rigorous prospective studies have not been done.

Cephalosporins can enter breast milk and may alter bowel flora of the infant. Thus, use during breastfeeding is often discouraged.

Adverse Effects of Cephalosporins

Significant adverse effects of cephalosporins include

Hypersensitivity reactions are the most common systemic adverse effects; rash is common, but immediate IgE-mediated urticaria and anaphylaxis are rare.

Cross-sensitivity between cephalosporins and penicillins is uncommon; cephalosporins can be given cautiously to patients with a history of delayed hypersensitivity to penicillin if necessary. However, cephalosporins should not be used in patients who have had an anaphylactic reaction to penicillin. Pain at the IM injection site and thrombophlebitis after IV use may occur.

Cefotetan may have a disulfiram-like effect when ethanol is ingested, causing nausea and vomiting. Cefotetan may also elevate the prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT), an effect that is reversible with vitamin K.

Drugs Mentioned In This Article

Drug Name Select Trade
Ceftobiprole No US brand name
azithromycin ZITHROMAX
Ceftriaxone ROCEPHIN
Ceftibuten CEDAX
disulfiram ANTABUSE
Cefotaxime CLAFORAN
vancomycin VANCOCIN
Cephalexin KEFLEX
Cefoxitin MEFOXIN
Cefixime SUPRAX

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