Cephalosporins

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, which 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 from inactivating 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 crucial resistance mechanism is 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, eg, ceftazidime/avibactam and ceftolozane/tazobactam.

Administration

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 effectively treats uncomplicated gonococcal infection or its complications, such as pelvic inflammatory disease or epididymo-orchitis.[8][9][10]

Fourth-generation: Cefepime is administered parenterally.

Fifth-generation: Ceftaroline is administered parenterally.

Many parenterally administered cephalosporins have short half-lives and need to be given more frequently in patients with normal renal function. Cefazolin and ceftriaxone have a longer half-life; thus, they do not need to be dosed 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.[11] 

Adverse Effects

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:

Hypersensitivity Reaction

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 allergic to penicillin might also show a hypersensitive reaction to cephalosporins. This cross-reactivity is 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.[12][13]

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 or the patient. However, if the patient starts making IgG antibodies against the drug, the antibody will bind to the red blood cell. The immune system will react with the abnormal red blood cells, resulting in hemolysis. Cefotetan and ceftriaxone are the two cephalosporins most likely to cause DIIHA.[14] 

Disulfiram-like Reaction 

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 cephalosporins to present with this reaction.[15]

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.[16] 

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, the synergistic nephrotoxicity of cephalosporin and aminoglycoside is not to be completely understood.[17][18]

Pseudomembranous Colitis

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.[19][17] 

Contraindications

One of the contraindications of cephalosporins is if patients are allergic to them or have had an anaphylactic reaction to penicillin or other beta-lactam antimicrobials. The cross-reactivity is thought to be due to similar side chains, not the beta-lactam ring.

Ceftriaxone is contraindicated in neonates with hyperbilirubinemia because of reports that ceftriaxone displaces bilirubin from albumin, increasing the free bilirubin concentrations and increasing the risk of jaundice in neonates.[20][21] Ceftriaxone reacts to a calcium-containing solution, and it can precipitate in the lungs and kidneys of infants less than 28 days old, which 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.[22] 

Monitoring

It is essential to monitor for possible signs of anaphylactic 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).[23] With other possible adverse reactions listed above, monitor CBC for 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. 

Toxicity

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.[24] Cefepime overdose can result in seizures and encephalopathy. Studies show it to potentially result 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 status and a triphasic wave discharge on electroencephalogram (EEG). Discontinuation of cefepime demonstrates normalization of mental status.[25][26]

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 clinicians, nurses, pharmacists, and other healthcare 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 for everyone, including the patient. Having clear roles between the different interprofessional team members and trusting each other can increase the team's efficiency. Crucial for team success is having effective communication skills. A clinician needs to be able to diagnose a disease accurately, 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 effects developing. A pharmacist can educate the patient on how to properly administer the drug and the other potential adverse effects, as well as verify agent selection and coverage and report any potential interactions to the ordering clinician. The patient also must tell the clinician 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 occur, resulting in better patient outcomes. [Level 5]