Continuing Education Activity
Cephalosporins are beta-lactam antimicrobials used to manage a wide range of infections from gram-positive and gram-negative bacteria. The five generations of cephalosporins are useful against skin infection, resistant bacteria, meningitis, and other infections. This activity describes the indications, contraindication, and possible adverse effects of cephalosporins, and will highlight the mechanism of action, adverse event profile, monitoring, route of administration, as well as other key factors.
- Identify the mechanism of action of cephalosporins.
- Describe the adverse effects and contraindications of cephalosporins.
- Review the toxicity of cephalosporins.
- Summarize interprofessional team strategies for improving care coordination and communication to advance cephalosporins and improve outcomes.
Cephalosporins are antimicrobials grouped into five generations based on their spectrum of coverage against gram-positive and gram-negative bacteria as well as their temporal discovery. First-generation cephalosporins have coverage against most gram-positive cocci as well as gram-negative bacteria, e.g., Escherichia coli (E. coli), Proteus mirabilis, and Klebsiella pneumoniae. Second-generation cephalosporins have coverage against Haemophilus influenza (H. influenza), Moraxella catarrhalis, and Bacteroides spp. Third-generation cephalosporins have less coverage against most gram-positive organisms but have increase coverage against Enterobacteriaceae, Neisseria spp., and H. influenza. Fourth-generation cephalosporins have similar coverage as third-generation cephalosporins but with additional coverage against gram-negative bacteria with antimicrobial resistance, e.g., beta-lactamase. Fifth-generation cephalosporins have coverage against methicillin-resistant staphylococci and penicillin-resistant pneumococci.
First-generation cephalosporins include cefazolin, cephalothin, cephapirin, cephradine, cefadroxil, and cephalexin. First-generation cephalosporins have active coverage against most gram-positive cocci such as staphylococci spp.and streptococci spp.while having minimal coverage against gram-negative bacteria. Gram-negative bacteria that are more susceptible to first-generation cephalosporins are Proteus mirabilis, E. coli, and Klebsiella pneumoniae. Oral first-generation cephalosporins are commonly prescribed to use against uncomplicated skin and soft tissue infections such as cellulitis and abscesses commonly due to a staphylococci spp. or streptococci spp. infection. Additionally, clinicians can also use them for bone, respiratory tract, genitourinary tract, biliary tract, bloodstream infection, otitis media, and surgical prophylaxis. In fact, cefazolin is the cephalosporin of choice for surgical prophylaxis. One of the non-FDA approved indication is to use first-generation cephalosporins for endocarditis prophylaxis for those who are susceptible and undergoing a dental or respiratory procedure.
Second-generation cephalosporins divide into two subgroups: the second-generation and the cephamycin subgroup. Some of the second-generation subgroups include cefuroxime and cefprozil. The cephamycin subgroup includes cefmetazole, cefotetan, and cefoxitin. Within the first subgroup, cefuroxime has increase coverage against H. influenza. Indications for cefuroxime also include Lyme disease in pregnant women and children. The cephamycin subgroup has increased coverage against Bacteroides species. Second-generation cephalosporins have less activity against gram-positive cocci compared to the first-generation cephalosporins but have increase activity against gram-negative bacilli. They are often prescribed to treat respiratory infections such as bronchiolitis or pneumonia. Other indications for second-generation cephalosporins are similar to first-generation indications (bone, respiratory tract, genitourinary tract, biliary tract, bloodstream infection, otitis media, and surgical prophylaxis). In addition to the gram-negative bacteria covered by first-generation cephalosporins, second-generation cephalosporins also have coverage against H. influenza, Enterobacter aerogenes, Neisseria species, and Serratia marcescens.
Third-generation cephalosporins include cefotaxime, ceftazidime, cefdinir, ceftriaxone, cefpodoxime, and cefixime. This generation has extended gram-negative bacteria coverage often used to treat gram-negative infection resistant to the first and second generation or other beta-lactams antimicrobials. When given IV, third-generation can penetrate the blood-brain barrier and cover bacteria in the cerebral spinal fluid, especially ceftriaxone and cefotaxime. Ceftriaxone can be given to treat meningitis caused by H. influenza, Neisseria meningitidis, or Streptococcus pneumoniae. Ceftriaxone is also used to treat gonorrhea and disseminated Lyme disease. Ceftazidime, very importantly, has Pseudomonas aeruginosa coverage.
Fourth-generation cephalosporin includes cefepime. Cefepime is a broad-spectrum antimicrobial that can penetrate the cerebral spinal fluid. Cefepime has an additional quaternary ammonium group, which allows them to penetrate the outer membrane of gram-negative bacteria better. Similar to the activity of cefotaxime and ceftriaxone, cefepime can cover Streptococcus pneumoniae and methicillin-sensitive Staphylococcus aureus (MSSA). Similar to ceftazidime, cefepime, very importantly, can cover for Pseudomonas aeruginosa. In addition to the gram-negative bacteria that third-generation covers (Neisseria spp., H. influenza, and Enterobacteriaceae), cefepime can coverage against beta-lactamase-producing gram-negative bacilli. Although effective against both gram-positive and gram-negative bacteria, cefepime is reserved for serious systemic infection in patients who are likely to have multi-resistance organisms.
Fifth-generation cephalosporins include ceftaroline. Ceftaroline is also a broad-spectrum antimicrobial thus can cover susceptible gram-positive and gram-negative organisms. However, what makes it unique from the rest of the cephalosporins is that it has coverage against methicillin-resistant Staphylococcus aureus (MRSA). Ceftaroline can also cover Listeria monocytogenes and Enterococcus faecalis. However, ceftaroline does not cover Pseudomonas aeruginosa.
Mechanism of Action
Bacteria synthesize a cell wall that is strengthened by cross-linking peptidoglycan units via penicillin-binding proteins (PBP, peptidoglycan transpeptidase). Initially derived from the fungus Cephalosporium sp., cephalosporins are a large group of bactericidal antimicrobials that work via their beta-lactam rings. The beta-lactam rings bind to the penicillin-binding protein and inhibit its normal activity. Unable to synthesize a cell wall, the bacteria die.
Staphylococcus aureus that is initially susceptible to cephalosporins can develop resistance by changing the structure of the penicillin-binding proteins. S. aureus does this by having a gene that encodes a modified penicillin-binding protein; this prevents the cephalosporin’s beta-lactam rings to inactivate the protein. The bacterium that develops this mechanism of resistance is called methicillin-resistant Staphylococcus aureus (MRSA). As indicated above, out of the five generations of cephalosporin, only the fifth generation ceftaroline has coverage against methicillin-resistant Staphylococcus aureus. Another very important mechanism of resistance is by producing the enzyme beta-lactamase, which cleaves the beta-lactam ring preventing it from attaching to the penicillin-binding proteins, e.g., peptidoglycan transpeptidase. Beta-lactamase inhibitors can be co-formulated with cephalosporins to increase their spectrum of activity, e.g., ceftazidime/avibactam, and ceftolozane/tazobactam.
First-generation: Cefazolin, cephalothin, and cephapirin are administered parenterally. The administration route for cefadroxil and cephalexin is oral. Cephradine administration can be parenteral or oral.
Second-generation: Cefuroxime can be administered parenterally or orally. Cefprozil administration is oral. Cefmetazole, cefotetan, and cefoxitin are administered parenterally.
Third-generation: Cefotaxime, ceftazidime, and ceftriaxone administration is via the parenteral route. Cefdinir, cefixime, and cefpodoxime are administered orally. A single intramuscular shot of 125 or 250 mg of ceftriaxone is an effective treatment of uncomplicated gonococcal infection or its complications such as pelvic inflammatory disease or epididymo-orchitis.
Fourth-generation: cefepime is administered parenterally.
Fifth-generation: Ceftaroline is administered parenterally.
Many of the parenterally administered cephalosporins have short half-lives and need to given more frequently in patients with normal renal function. Cefazolin and ceftriaxone have longer half-life; thus, they do not need to dose as often. Ceftriaxone is the only cephalosporin that does not need to have its dose modified in the presence of renal failure. However, in patients with both renal and hepatic impairment, the recommended daily dose should not exceed 2 g.
Cephalosporins have low toxicity and are generally safe. The most common adverse reactions from cephalosporins are nausea, vomiting, lack of appetite, and abdominal pain.
The less common adverse reaction includes:
A hypersensitivity reaction to cephalosporin is infrequent and is more common in first and second-generation cephalosporins. Common allergic reaction to cephalosporin includes rash, hives, and swelling. Rarely will the hypersensitivity reaction result in anaphylaxis. Patients who are allergic to penicillin might show a hypersensitive reaction to cephalosporins as well. This cross-reactivity is once again more common in first and second-generation cephalosporins because they have R-groups more similar to penicillin G. Third generation and beyond show minimal cross-reactivity.
Drug-induce Immune Hemolytic Anemia (DIIHA)
The proposed mechanism of action of DIIHA is that the drug binds to the red blood cell membrane; this causes no harm to the red blood cell itself nor the patient. However, if the patient starts making IgG antibodies against the drug, the antibody will bind the red blood cell. The immune system will react with the abnormal red blood cell resulting in hemolysis. Cefotetan and ceftriaxone are the two cephalosporins most likely to cause DIIHA.
Cephalosporins containing a methyltetrazolethiol side chain can inhibit the aldehyde dehydrogenase enzyme resulting in the accumulation of acetaldehyde. Cefamandole, cefoperazone, and moxalactam are the most common cephalosporin to present with this reaction.
Vitamin K Deficiency
Certain cephalosporins can inhibit vitamin K epoxide reductase, preventing the production of the reduced(active) vitamin K. Therefore, there is a decreased synthesis of coagulation factors, and the patient is predisposed to hypoprothrombinemia.
Increase Nephrotoxicity of Aminoglycosides
There are reported cases of drug-induced nephrotoxicity when patients take cephalosporin and aminoglycosides in combination, but other factors often cloud the evidence. Therefore, synergistic nephrotoxicity of cephalosporin and aminoglycoside is not to be completely understood.
Pseudomembranous colitis is often associated with the use of clindamycin and ampicillin. Cephalosporin use is also a common cause of pseudomembranous colitis, especially third-generation cephalosporins.
One of the contraindications of cephalosporin is if patients are allergic to them or those that have had an anaphylactic reaction to penicillin or other beta-lactams antimicrobials.
Ceftriaxone is contraindicated in hyperbilirubinemic neonates because of reports that ceftriaxone displaces bilirubin from albumin, increasing the free bilirubin concentrations and increases the risk of jaundice in neonates. Ceftriaxone reacts to calcium-containing solution and it can precipitate in lungs and kidneys of infants less than 28 days old and this could be life-threatening. Therefore, ceftriaxone is also contraindicated in infants less than 28 days old if they are expected to receive any calcium-containing products.
It is essential to monitor for possible signs of anaphylaxic reaction as well as allergic reactions such as hives, itching, and swelling. Physicians and pharmacists also need to monitor renal function periodically because that could potentially warrant a change in the dose and/or dosing frequency of the cephalosporin (except for ceftriaxone). With other possible adverse reactions listed above, monitor CBC for possible signs of drug-induced immune hemolytic anemia or hypoprothrombinemia from vitamin K deficiency. Also, monitor for possible signs of a disulfiram-like reaction or pseudomembranous colitis.
Testing the effects of high dosage cephalosporin in rabbits, there is new evidence of nephrotoxicity due to its effect on the mitochondria system of the kidney. Cefepime overdose can result in seizures and encephalopathy. Studies show it to potentially be from cefepime crossing the blood-brain barrier and displaying concentration-dependent ϒ-aminobutyric acid (GABA) antagonism, which can also occur with toxic doses of penicillin G. Other studies show altered mental statues and a triphasic wave discharge on electroencephalogram (EEG). Discontinuation of cefepime demonstrates normalization of mental status.
Exercise caution with cephalosporin treatment in patients with a history of seizures, especially with poor renal function.
Enhancing Healthcare Team Outcomes
Effective interprofessional teamwork and coordination by physicians, nurses, pharmacists, and other health care professionals are required to provide the best care for the patient. One of the principles that enhance healthcare team outcomes is having a shared goal by everyone, including the patient. Having clear roles between the different members and trusting each other can increase the team’s efficiency. Crucial for team success is having effective communication skills. A physician needs to be able to accurately diagnose a disease and prescribe the proper medication and inform possible adverse effects to the patients. Nurses also need to know possible adverse effects so that they can inform the physician if they notice any adverse effect developing. A pharmacist can educate the patient on how to properly administer the drug as well as the other potential adverse effects, as well as verifying agent selection and coverage, and reporting any potential interactions to the ordering clinician. The patient also must tell the physician and nurse what they are experiencing anything unusual so that everyone is informed about the patient's well-being. Through effective interprofessional healthcare teamwork, appropriate management of cephalosporin adverse drug reactions can take place, resulting in better patient outcomes. [Level 5]