Cephalosporins are bactericidal beta-lactam antibiotics. They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell wall synthesis. There are multiple generations of cephalosporins.
(See also Overview of Antibacterial Medications.)
Cephalosporins
Medication | Route |
|---|---|
First generation | |
Cefadroxil | Oral |
Cefazolin | Parenteral |
Cephalexin | Oral |
Cephradine | Oral |
Second generation | |
Cefaclor | Oral |
Cefotetan* | Parenteral |
Cefoxitin* | Parenteral |
Cefprozil | Oral |
Cefuroxime | Parenteral or oral |
Third generation | |
Cefdinir | Oral |
Cefditoren | Oral |
Cefixime | Oral |
Cefoperazone/sulbactam (not available in the United States) | Parenteral |
Cefotaxime | Parenteral |
Cefpodoxime | Oral |
Ceftazidime | Parenteral |
Ceftazidime/avibactam | Parenteral |
Ceftibuten | Oral |
Ceftriaxone | Parenteral |
Fourth generation | |
Cefepime | Parenteral |
Anti-MRSA cephalosporins | |
Ceftaroline/fosamil | Parenteral |
Ceftobiprole/medocaril | Parenteral |
Other cephalosporins | |
Cefiderocol | Parenteral |
Ceftolozane/tazobactam | Parenteral |
* Also classified as a cephamycin. | |
MRSA = methicillin-resistant Staphylococcus aureus. | |
Pharmacokinetics for Cephalosporins
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
Ceftriaxone
Cefotaxime
Ceftazidime
Cefepime
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:
Gram-positive bacteria
Cephalosporins are classified in generations (see table Some Clinical Uses of Third- and Fourth-Generation Cephalosporins). The first-generation cephalosporins are effective mainly against gram-positive organisms. Higher generations generally have expanded spectra against aerobic gram-negative bacilli. The cephalosporins ceftaroline and ceftobiprole are active against methicillin-resistantStaphylococcus aureus (MRSA).
Cephalosporins have the following limitations:
Lack of activity against enterococci
Lack of activity against methicillin-resistant staphylococci (except for ceftaroline and ceftobiprole)
Lack of activity against anaerobic gram-negative bacilli(except for cefotetan and cefoxitin)
First-generation cephalosporins
These cephalosporins have excellent activity against
Gram-positive cocci
Certain gram-negative bacilli
Oral first-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 forendocarditis due to methicillin-sensitive S. aureus and for prophylaxis before cardiothoracic, orthopedic, abdominal, and pelvic surgery.
Depending on local susceptibility, the gram-negative bacillus Escherichia colican be sensitive, and cephalexin is frequently used for uncomplicated urinary tract infections.
Second-generation cephalosporins and cephamycins
Second-generation cephalosporins are active against
Gram-positive cocci
Certain gram-negative bacilli
Cephamycins are antibiotics that were originally produced by Streptomyces but are now synthetic. They are typically classed with second-generation cephalosporins. Cephamycins are more active against anaerobes, such as
Bacteroides species, including Bacteroides fragilis
Second-generation cephalosporins may be slightly less active against gram-positive cocci than first-generation cephalosporins. Second-generation cephalosporins and cephamycins are sometimes used for polymicrobial infections that include gram-negative bacilli and gram-positive cocci. Because cephamycins can be active against Bacteroides species, they had been used when anaerobes were suspected (eg, in intra-abdominal sepsis, decubitus ulcers, or diabetic foot infections). However, these bacilli are no longer reliably susceptible to cephamycins, so cephamycins are no longer recommended for empiric use in intra-abdominal infections (1, 2).
Third-generation cephalosporins
These cephalosporins are active against
Haemophilus influenzae and most Enterobacterales (formerly Enterobacteriaceae; eg, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis) that do not produce AmpC beta-lactamase or extended-spectrum beta-lactamase (ESBL)
Most third-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 againstS. aureus and, if used for skin and soft-tissue infections, should be restricted to uncomplicated infections due to streptococci.
Ceftazidime and cefoperazone are active againstPseudomonas aeruginosa, whereas the rest of the class is not. Both are also active against Streptococcus species. Ceftazidimehas poor activity against gram-positive species and is inappropriate for staphylococci infections. Adding avibactam to ceftazidime increases its spectrum to include Enterobacterales that produce AmpC, ESBL, orKlebsiella pneumoniae carbapenemase (KPC).
These cephalosporins have many clinical uses, as do the fourth-generation cephalosporins (see table Some Clinical Uses of Third- and Fourth-Generation Cephalosporins).
Fourth-generation cephalosporins
The fourth-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 Enterobacterales, such asEnterobacter species
Some Clinical Uses of Third- and Fourth-Generation Cephalosporins
Cephalosporin | Indications | Comments |
|---|---|---|
Third- and fourth-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 antibiotics to cover anaerobes or enterococci |
Ceftriaxone and some other third-generation cephalosporins | Used with a macrolide or fluoroquinolone to cover atypical pathogens (mycoplasmas, Chlamydophila species, Legionella species) | |
Cefotaxime Ceftriaxone | Acute meningitis suspected to be due to Streptococcus pneumoniae, Haemophilus influenzae, or Neisseria meningitidis | Used with ampicillin to coverListeria monocytogenesand with vancomycin to coverS. 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 |
Ceftazidime, cefepime | Hospital-acquired pneumonia and ventilator-associated pneumonia Empiric therapy for postneurosurgical meningitis to cover Pseudomonas aeruginosa | Used with vancomycin to cover methicillin-resistantS. aureus |
Ceftriaxone | 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 | Oral doxycycline added when coinfection with chlamydia has not been excluded | |
* 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 third-generation cephalosporins. | ||
HACEK = Haemophilus species, Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. | ||
Anti-MRSA cephalosporins
The anti-MRSA (sometimes referred to as fifth-generation) cephalosporins ceftaroline and ceftobiprole are active against
Methicillin-resistant S. aureus (MRSA)
Penicillin-resistant streptococci
Their activity against other gram-positive cocci and gram-negative bacilli is similar to that of third-generation cephalosporins. The anti-MRSA cephalosporins are not active against Pseudomonas species.
Other cephalosporins
Cefiderocol is a novel siderophore cephalosporin with activity against many resistant gram-negative bacteria includingPseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, and most enteric gram-negative bacteria (eg, E. coli , Klebsiella species) including those that produce extended-spectrum beta-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs), and metallo-beta-lactamases (MBLs). Because of this broad spectrum of activity against challenging gram-negative pathogens, cefiderocol is often reserved for definitive therapy of invasive infections against such pathogens. Cefiderocol has no activity against gram-positive bacteria or anaerobes.
Ceftolozane/tazobactam is an advanced-generation cephalosporin primarily used for its activity against multidrug resistantP. aeruginosa; however, it also has activity against most enteric gram-negative bacteria, some anaerobes, and streptococci. Ceftolozane/tazobactam is active against some ESBL–producing or AmpC beta-lactamase–producing strains.
Indications references
1. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surg Infect (Larchmt). 2010;11(1):79-109. doi:10.1089/sur.2009.9930
2. Mazuski JE, Tessier JM, May AK, et al. The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection. Surg Infect (Larchmt). 2017;18(1):1-76. doi:10.1089/sur.2016.261
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. About 2% of penicillin-allergic patients have cross-reactivity with cephalosporins (1, 2). Cross-sensitivity with penicillin allergy is not the same for all cephalosporins—it depends on the specific chemical and structural features. The use of third- or fourth-generation cephalosporins or cephalosporins with dissimilar R1 side chains than the offending penicillin has a negligible risk of cross allergy; cefazolin, in particular, has a unique side chain and very low cross-reactivity. 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 (3, 4, 5).
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. 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 neonates who are hyperbilirubinemic and preterm because, in vitro, this antibiotic can displace bilirubin from serum albumin, potentially triggeringkernicterus.
Contraindications references
1. Shenoy ES, Macy E, Rowe T, Blumenthal KG: Evaluation and management of penicillin allergy: A review. JAMA 321(2):188–199, 2019. doi: 10.1001/jama.2018.19283
2. Campagna JD, Bond MC, Schabelman E, Hayes BD: The use of cephalosporins in penicillin-allergic patients: A literature review. J Emerg Med 42(5):612–620, 2012. doi: 10.1016/j.jemermed.2011.05.035
3. 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
4. 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
5. 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 of Cephalosporins 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 microbiota of the infant. Thus, use during breastfeeding is often discouraged.
Adverse Effects of Cephalosporins
Significant potential adverse effects of cephalosporins include
Hypersensitivity reactions (most common)
Clostridioides (formerly Clostridium) difficile–induced diarrhea (pseudomembranous colitis)
Positive Coombs test (although hemolytic anemia is very uncommon)
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 (1). Pain at the IM injection site and thrombophlebitis after IV use may occur.
Cefotetan may have a disulfiram-like effect whenethanol 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.
Adverse effects reference
Zagursky RJ, Pichichero ME: Cross-reactivity in β-lactam allergy. J Allergy Clin Immunol Pract 6(1):72–81.e1, 2018. doi: 10.1016/j.jaip.2017.08.027
