Cephalexin

Mechanism of Action

Cephalexin is a beta-lactam antibiotic that belongs to the first-generation cephalosporin class and is characterized by a beta-lactam ring in its structure. Within a bacterial cell, peptidoglycan provides mechanical stability to the cell wall. Cephalexin, along with other beta-lactam antibiotics, utilizes its beta-lactam ring to inhibit the synthesis of peptidoglycan, a crucial process in forming the bacterial cell wall. 

More specifically, the beta-lactam ring of cephalexin binds to penicillin-binding proteins (PBPs), which effectively hinders the final stage of peptidoglycan synthesis, known as the transpeptidation reaction. This reaction is crucial for the cross-linking of bacterial peptidoglycan. By inhibiting this process, cephalexin disrupts cell viability, ultimately resulting in bacterial cell autolysis.[6]

Although this mechanism of cephalexin inhibits a crucial step in preserving the bacterial cell wall, bacteria can develop resistance to this antibiotic through various mechanisms, as listed below.

• The primary resistance mechanism involves bacterial expression of enzymes "beta-lactamases" that degrade beta-lactam antibiotics such as cephalexin.
• Moreover, bacteria can acquire resistance to cephalexin by modifying the PBPs, thereby altering the binding affinity of cephalexin to its target site.
• In addition, bacteria can synthesize efflux pumps that can expel cephalexin from within the bacterial cell.[6]

Pharmacokinetics

Absorption: Cephalexin is rapidly absorbed in adults and can be taken with or without food, as it is acid-stable.

Time of peak plasma concentration: Cephalexin reaches its peak plasma concentration within 1 hour.

Distribution: Cephalexin is widely distributed throughout most body fluids.

Plasma protein binding: Approximately 10% to 15% of cephalexin binds to plasma proteins.

Metabolism: Cephalexin, like other cephalosporins, does not significantly affect hepatic CYP450 enzymes. As a result, the potential for drug-drug interactions while administering cephalexin is drastically limited.[7]

Excretion: Approximately 90% of the unchanged drug is excreted in the urine. This characteristic makes cephalexin particularly effective in treating urinary tract infections.

Administration

Cephalexin is available in capsule form and can be administered orally at 250 or 500 mg doses. The recommended dosage is typically 1 to 4 times daily, usually for 7 days. Cephalexin should be administered on an empty stomach, as it exhibits better absorption in this environment. Patients often report that cephalexin capsules exhibit an unpleasant taste and notably large size, posing difficulty in swallowing.[1]

Cephalexin is also available in tablet form, with 250 or 500 mg tablet options. In addition, an oral suspension of cephalexin is available in 250 mg per 5 mL strength, which should be shaken well before administration and stored in the refrigerator between doses.

For oral administration of cephalexin in capsules or suspension, the recommended daily dosage is as follows:

• Adults and children 15 years and older: Dosing ranges from 1000 to 4000 mg, divided into multiple doses.
• Children 1 year and older: Dosing is determined based on the child's weight. The usual dosage range is between 25 and 100 mg per kg body weight per day, divided into multiple doses.[8]

Specific Patient Populations

Hepatic Impairment: The manufacturer label does not provide specific dose adjustment guidance for cephalexin for patients with hepatic impairment.

Renal Impairment: For patients with renal impairment, caution is advised by the manufacturer while using cephalexin, especially in cases of severe impairment (creatinine clearance, CrCl,  <30 mL/min) with or without dialysis. A dose reduction might be necessary in case of clinical observation and regular monitoring of renal function.

The manufacturer's recommendations for cephalexin dosages for patients with renal impairment are listed below. 

• CrCL ≥60 mL/min: No dose adjustment is necessary.
• CrCL 30 to 59 mL/min: No dose adjustment is required, but the maximum daily dose should not exceed 1 g.
• CrCL 15 to 29 mL/min: A dosage of 250 mg is recommended, administered every 8 or 12 hours.
• CrCL 5 to 14 mL/min (not yet on dialysis*): A dosage of 250 mg is recommended, administered every 24 hours.
• CrCL 1 to 4 mL/min (not yet on dialysis*): A reduced dosage of 250 mg is recommended, administered every 24 or 60 hours.

*Note: The term "not yet on dialysis" indicates patients who have not yet started undergoing dialysis treatment for renal failure.

Pregnancy: In pregnant women, cephalexin is classified as a pregnancy category B medicine. Although no adequate and well-controlled studies have been conducted specifically on pregnant women, animal studies on mice and rats have not shown any evidence of fertility impairments or harm to the fetus.

Pediatric patients: Cephalexin has been deemed safe and effective for pediatric patients. Therefore, it is recommended to calculate the total daily dosage of oral cephalexin capsules based on the body weight of pediatric patients, ranging from 25 to 50 mg per kg, before administering the drug. Cephalexin should be divided into equal dosages and administered for 7 to 14 days. The maximum daily dosage should not exceed 4 g.

Breastfeeding: Due to the presence of cephalexin in breast milk, caution is advised during cephalexin therapy for nursing mothers, as the manufacturer recommends.[9]

Older patients: No dose adjustment is necessary, as safety and efficacy are already established. However, considering that this drug is primarily excreted through the kidneys, it is advisable to consider a dose adjustment for older patients with impaired renal function.

Adverse Effects

The adverse effects reported by drug manufacturers associated with cephalexin include abdominal pain, diarrhea, dyspepsia, gastritis, nausea, vomiting, erythema multiforme, genital pruritus, vaginitis, vaginal discharge, candidiasis, thrombocytopenia, neutropenia, eosinophilia, arthralgia, arthropathy, and arthritis.[1]

Clinical trials have reported increased serum alanine aminotransferase, increased serum aspartate aminotransferase, cholestatic jaundice, and interstitial nephritis in patients using cephalexin.

Another aspect of cephalexin administration is the potential for allergic reactions to the drug. Patients who have been administered penicillin earlier may develop an allergy to cephalexin. These reactions occur when a patient's immune system generates IgG or IgM antibodies in response to penicillin, which can potentially bind to cephalexin when taken orally. The literature does not support the claim that about 10% of penicillin-allergic patients have cross-reactions to cephalosporin antibiotics. Retrospective studies suggest that the incidence of allergic or immunologic reactions to cephalosporins after the administration of penicillin is only around 1% to 3%.[10]

Patients taking cephalexin have reported cases of Clostridioides difficile–associated diarrhea (CDAD) and colitis. Diarrhea can occur at the beginning of cephalexin administration and up to 3 months after treatment. Older individuals and those with compromised immune systems are at an increased risk of developing CDAD following long-term antibiotic treatments.[11]

Immunogenic hemolytic anemia, although rare, has been reported, particularly in patients with hypersensitivity reactions to other cephalosporins.[12][13] Other hypersensitivity reactions that have been reported include skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms.[14] Although cephalexin generally has few adverse effects, rare occurrences of toxic tendinopathy have been reported. Moreover, a clinical case study has documented other rare adverse effects of cephalexin, such as drug-induced acute generalized exanthematous pustulosis.[15]

Drug Interactions

Like many other medications, cephalexin can interact with other drugs, potentially affecting their efficacy or safety. Therefore, it is essential to be aware of potential drug interactions when prescribing or administering cephalexin to ensure optimal patient outcomes.

• Metformin: Coadministration of cephalexin with metformin may result in increased plasma concentration and decreased renal clearance of metformin. Close monitoring of patients is advised, and adjustments to the metformin dose may be necessary when cephalexin and metformin are administered together.

• Probenecid: Coadministration of cephalexin with probenecid is not recommended as it may inhibit the renal excretion of cephalexin. Studies have shown that probenecid can extend and flatten the plasma concentration–time curve of cephalexin, thereby increasing the likelihood of achieving optimal pharmacokinetic and pharmacodynamic targets. However, the simultaneous use of cephalexin and probenecid may benefit specific patient populations.[16]

Contraindications

Cephalexin and other cephalosporins are contraindicated in patients with a penicillin allergy, as this increases the risk of allergic reactions.[10] Cephalexin is also contraindicated in individuals with hypersensitivity to cephalexin or other medications in the cephalosporin class.

Monitoring

Peak serum concentrations of cephalexin are typically observed approximately 1 hour following a single dose. Although the serum half-life ranges from 1 to 2 hours, patients with significantly reduced CrCL levels may experience a prolonged half-life of up to 22 hours. Patients undergoing hemodialysis may experience an extended half-life of approximately 4 to 5 hours. Cephalexin should be taken on an empty stomach to optimize absorption, as food intake delays drug onset and reduces peak concentration. Moreover, consuming cephalexin with food can extend the detection time of the drug in the serum.[1] 

Furthermore, patients with renal impairment may experience prolonged excretion rates of cephalexin due to its unchanged elimination by the kidneys.[1][17] Therefore, monitoring renal function in these patients and considering dose adjustment accordingly is important.

Blood sugar levels should be monitored when administering cephalexin to a patient taking metformin, as there is an elevated risk of hypoglycemia in those cases.

Cephalosporins, including cephalexin, might cause a prolongation in prothrombin time. Consequently, clinicians should carefully monitor prothrombin time, particularly in patients with malnutrition, renal or hepatic impairment, undergoing anticoagulation treatment, or receiving chronic antibiotic therapy.

Toxicity

Cephalexin is associated with a relatively low incidence of adverse effects in patients when the drug is administered correctly and safely. However, in cases of toxicity or overdose, adverse effects may include soreness of the oral cavity, pruritus of pregnancy, and gastrointestinal symptoms such as nausea, vomiting, epigastric distress, diarrhea, and hematuria.[1] Furthermore, there have been only a few sporadic documented cases of cephalexin leading to fatal episodes of Stevens-Johnson syndrome and toxic epidermal necrolysis.[18]

In the event of an overdose, it is advisable to implement general supportive measures. However, the effectiveness of interventions such as charcoal hemoperfusion, forced diuresis, peritoneal dialysis, and hemodialysis in treating cephalexin overdose has not been established yet. To obtain the most up-to-date protocol for managing cephalexin overdose, it is recommended to contact the local drug poison center.

Enhancing Healthcare Team Outcomes

Interprofessional healthcare team members must be aware of the possibility of bacterial resistance to cephalexin. When cephalexin is administered to a patient with an infection that exhibits resistance to the drug, it poses a risk of subjecting the patient to potential adverse effects without effectively treating the infection. This can hinder effective infection management and increase the likelihood of developing antibiotic resistance.

Healthcare teams must carefully consider the potential for drug-induced allergic reactions when administering cephalexin. The most common manifestations of such reactions with cephalexin are urticaria and maculopapular exanthema.[18] Nurses should inform patients of the possible adverse reactions associated with cephalexin and guide how to manage them. In cases of uncertainty, patients should be advised to contact their clinicians. Pharmacists should conduct medication reconciliation to ensure accurate dosing and the absence of potential drug interactions. Both nurses and pharmacists can offer patients valuable medication counseling to minimize the risks associated with cephalexin administration.

Other significant and potentially life-threatening complications associated with cephalexin are Stevens-Johnson syndrome and toxic epidermal necrolysis. Although these complications are infrequent, healthcare providers must recognize the presenting symptoms, which typically include an extensive erythematous rash followed by widespread epidermal sloughing. In Stevens-Johnson syndrome and toxic epidermal necrolysis, the drug reaction can manifest as late as 1 to 3 weeks after the drug initiation. However, it is essential to note that these drug reactions can occur sooner than 1 to 3 weeks, presenting as conjunctivitis or lesions on mucosal membranes. Stevens-Johnson syndrome may also present with flu-like symptoms, including cough, arthralgias, myalgias, and fever. These symptoms can subsequently progress to extensive ulcerations on various body surfaces and multisystem organ failure, potentially resulting in death. Immediate discontinuation of cephalexin administration is paramount to prevent further progression and complications.[18]

By collaborating and developing a collective understanding of identifying adverse drug reactions to cephalexin, the clinical team can effectively intervene and discontinue drug administration before severe complications arise. This necessitates open communication channels and shared decision-making capabilities among all interprofessional team members. Educating healthcare professionals on these matters fosters an environment that prioritizes patient safety and delivers high-quality care. The interprofessional management of cephalexin therapy, with the involvement of physicians, advanced practice practitioners, nursing staff, and pharmacists operating as a cohesive healthcare administration unit, will contribute to improved patient outcomes.