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Cephalosporins

By

Brian J. Werth

, PharmD, University of Washington School of Pharmacy

Last full review/revision May 2022| Content last modified Sep 2022
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Cephalosporins are bactericidal beta-lactam antibiotics Beta-Lactams Beta-lactams are antibiotics that have a beta-lactam ring nucleus. Subclasses include Carbapenems Cephalosporins and cephamycins (cephems) Clavams Monobactams read more . They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell wall synthesis. There are 5 generations of cephalosporins.

Table

Pharmacokinetics

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:

Cephalosporins are classified in generations (see table Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins 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 Staphylococcal Infections Staphylococci are gram-positive aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia, endocarditis, and osteomyelitis... read more Staphylococcal Infections . Cephalosporins have the following limitations:

First-generation cephalosporins

These drugs have excellent activity against

  • Gram-positive cocci

Parenteral cefazolin is frequently used for endocarditis Infective Endocarditis Infective endocarditis is infection of the endocardium, usually with bacteria (commonly, streptococci or staphylococci) or fungi. It may cause fever, heart murmurs, petechiae, anemia, embolic... read more Infective 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 Sepsis and Septic Shock Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection. In septic shock, there is critical reduction in tissue perfusion; acute failure... read more , decubitus ulcers Pressure Injuries Pressure injuries are areas of necrosis and often ulceration (also called pressure ulcers) where soft tissues are compressed between bony prominences and external hard surfaces. They are caused... read more Pressure Injuries , or diabetic foot infections Diabetic Neuropathy In patients with diabetes mellitus, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular)... read more Diabetic Neuropathy ). 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 and cefoperazone are active against Pseudomonas aeruginosa Pseudomonas and Related Infections Pseudomonas aeruginosa and other members of this group of gram-negative bacilli are opportunistic pathogens that frequently cause hospital-acquired infections, particularly in ventilator... read more , whereas the rest of the class is not. Both are also active against Streptococcus species and methicillin-sensitive staphylococci. Adding avibactam to ceftazidime increases its spectrum to include Enterobacterales 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 Some Clinical Uses of 3rd- and 4th-Generation Cephalosporins 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 Enterobacterales, such as Enterobacter species

Table

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. About 2% of penicillin-allergic patients have cross-reactivity with cephalosporins (1 Contraindications references Cephalosporins are bactericidal beta-lactam antibiotics. They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell wall synthesis. There are 5 generations of cephalosporins... read more , 2 Contraindications references Cephalosporins are bactericidal beta-lactam antibiotics. They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell wall synthesis. There are 5 generations of cephalosporins... read more ). Cross-sensitivity with penicillin allergy is not the same for all cephalosporins—it depends on the specific chemical and structural features. The use of 3rd- or 4th-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 Contraindications references Cephalosporins are bactericidal beta-lactam antibiotics. They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell wall synthesis. There are 5 generations of cephalosporins... read more , 4 Contraindications references Cephalosporins are bactericidal beta-lactam antibiotics. They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell wall synthesis. There are 5 generations of cephalosporins... read more , 5 Contraindications references Cephalosporins are bactericidal beta-lactam antibiotics. They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell wall synthesis. There are 5 generations of cephalosporins... read more ).

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 hyperbilirubinemic and preterm neonates because, in vitro, ceftriaxone can displace bilirubin from serum albumin, potentially triggering kernicterus Kernicterus Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei. Normally, bilirubin bound to serum albumin stays in the intravascular space. However... read more .

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 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 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. 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.

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