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Cephalosporins, Classification and usage

Cephalosporins are bactericidal β-lactam antibiotics. They inhibit enzymes in the cell wall of susceptible bacteria, disrupting cell synthesis. There are 5 generations of cephalosporins

Pharmacology

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

• Ceftriaxone
• Cefotaxime
• Ceftazidime
• Cefepime

All cephalosporins penetrate poorly into ICF 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

Cephalosporins are bactericidal for most of the following:

• Gram-positive bacteria
• Gram-negative bacteria

Cephalosporins are classified in generations . 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 cephalosporin ceftaroline is active against methicillin-resistant Staphylococcus aureus. Cephalosporins have the following limitations:

• Lack of activity against enterococci (except for ceftaroline, which is active against Enterococcus faecalis, not E. faecium)
• Lack of activity against methicillin-resistant staphylococci (except for ceftaroline)
• Lack of activity against anaerobic gram-negative bacilli (except for cefotetan and cefoxitin)

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 active against

• Bacteroides sp, including B. fragilis

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 Bacteroidessp, they can be used when anaerobes are suspected (eg, in intra-abdominal sepsis, decubitus ulcers, and 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

• Haemophilus influenzae and some Enterobacteriaceae (eg, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis) that do not produce ampC β-lactamase or extended-spectrum β-lactamase (ESBL)

Ceftazidime is also active against

• Pseudomonas aeruginosa

Some 3rd-generation cephalosporins have relatively poor activity against gram-positive cocci. 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. These cephalosporins have many clinical uses, as does the 4th-generation cephalosporin.

Fourth-generation cephalosporin

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), ESBL-producing K. pneumoniae and E. coli, and ampC β-lactamase–producing Enterobacteriaceae, such as Enterobacter sp

Fifth-generation cephalosporin

The 5th-generation cephalosporin ceftaroline is active against

• Methicillin-resistant  aureus(MRSA) and E. faecalis

Its activity against other gram-positive cocci and gram-negative bacilli is similar to that of 3rd-generation cephalosporins. It is not active against Pseudomonas sp.

Contraindications

Cephalosporins are contraindicated in patients who are allergic to them or who have had an anaphylactic reaction to penicillins.

Ceftriaxone is contraindicated as follows:

• CeftriaxoneIV must not be coadministered with Ca-containing IV solutions (including continuous Ca-containing infusions such as parenteral nutrition) in neonates ≤ 28 days because precipitation of ceftriaxone-Ca salt is a risk. Fatal reactions with ceftriaxone-Ca precipitates in the lungs and kidneys of neonates have been reported. In some cases, different infusion lines were used, and ceftriaxone and Ca-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 Ca-containing IV solutions. However, because an interaction between ceftriaxone and IV Ca-containing solutions is theoretically possible in patients other than neonates, ceftriaxone and Ca-containing solutions should not be mixed or given within 48 h 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 Ca-containing products or on interaction between IM ceftriaxone and Ca-containing products (IV or oral) are available.
• Ceftriaxoneshould not be given to hyperbilirubinemic and preterm neonates because in vitro, ceftriaxone can displace bilirubin from serum albumin, potentially triggering kernicterus.

Use During Pregnancy and Breastfeeding

Cephalosporins are in pregnancy category B (animal studies show no risk and human evidence is incomplete, or animal studies show risk but human studies do not).

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

Adverse Effects

Significant adverse effects include

• Hypersensitivity reactions (most common)
• Clostridium difficile–induced diarrhea (pseudomembranous colitis—see Clostridium difficile–Induced Diarrhea)
• Leukopenia
• Thrombocytopenia
• 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. 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 PT/INR and PTT, an effect that is reversible with vitamin K.