Monograph of Cephalexin

Introduction

Cephalexin is a first‑generation cephalosporin antibiotic that has been widely utilized for the treatment of a variety of bacterial infections. The compound is chemically classified as a β‑lactam with a thienyl side chain, conferring resistance to many β‑lactamases produced by Gram‑positive organisms. Historically, cephalexin entered clinical use in the early 1970s as an orally available agent that could be administered in divided doses, providing an alternative to intravenous cephalosporins for outpatient therapy. The importance of cephalexin in pharmacology stems from its broad spectrum against Gram‑positive cocci, its predictable pharmacokinetic profile, and its role in antibiotic stewardship programs aimed at limiting the use of broader‑spectrum agents.

The primary objectives of this chapter are to:

• Describe the chemical and pharmacological characteristics of cephalexin.
• Explain the pharmacokinetic parameters and their clinical relevance.
• Outline therapeutic indications and dosage adjustments across patient populations.
• Illustrate clinical scenarios that demonstrate rational use of cephalexin.
• Summarize key take‑aways for clinical decision making.

Fundamental Principles

Core Concepts and Definitions

Cephalexin is a β‑lactam antibiotic that inhibits bacterial cell wall synthesis by binding to penicillin‑binding proteins (PBPs). This action prevents cross‑linking of peptidoglycan chains, leading to cell lysis. The drug is classified as a first‑generation cephalosporin, indicating its primary activity against Gram‑positive organisms and limited efficacy against many Gram‑negative bacilli.

Theoretical Foundations

The antibacterial effect of cephalexin is time‑dependent, meaning that the duration of drug exposure above the minimum inhibitory concentration (MIC) is more critical than peak concentration. Consequently, dosing schedules are designed to maintain serum concentrations above the MIC for a sufficient proportion of the dosing interval, typically ≥60% of the interval for optimal efficacy.

Key Terminology

• MIC (Minimum Inhibitory Concentration) – Lowest concentration that inhibits visible bacterial growth.
• C_max – Peak plasma concentration reached after a dose.
• T_max – Time to reach C_max.
• t_1/2 – Elimination half‑life of the drug.
• CL – Clearance, the volume of plasma from which the drug is completely removed per unit time.
• AUC – Area under the plasma concentration‑time curve, representing overall drug exposure.
• Renal Clearance – Portion of drug eliminated unchanged by the kidneys.
• Bioavailability – Fraction of orally administered dose that reaches systemic circulation.

Detailed Explanation

Chemical Structure and Synthesis

Cephalexin possesses a β‑lactam core fused to a dihydrothiazine ring, with a thienyl side chain at the 7‑position. The presence of an amino group at the 3‑position confers enhanced activity against Gram‑positive organisms. 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Mechanism of Action

Cephalexin binds with high affinity to PBPs 1 and 3 on the bacterial cell wall. This inhibits transpeptidase activity required for cross‑linking of the peptidoglycan layer. The resulting weakening of the wall leads to osmotic lysis. The drug’s activity is largely unaffected by the presence of the bacterial outer membrane, a feature that distinguishes it from many Gram‑negative‑specific agents.

Pharmacodynamics

Time above MIC (T>MIC) is the principal determinant of cephalexin efficacy. For most Gram‑positive organisms, maintaining plasma concentrations above the MIC for at least 60% of the dosing interval yields optimal bacteriostatic activity. In some cases, such as severe infections, a higher T>MIC threshold (≥80%) may be targeted, which can be achieved by more frequent dosing or higher doses.

Pharmacokinetics

Absorption

Cephalexin is well absorbed orally, with a bioavailability of approximately 90%. Peak plasma concentrations (C_max) are typically reached within 1–2 hours (T_max). The drug is stable in gastric acid, allowing for absorption without the need for acid suppression therapy.

Distribution

Distribution volume approximates 0.2 L/kg, reflecting moderate tissue penetration. The drug is largely unbound in plasma, with protein binding <5%. Distribution to exudative tissues, such as skin and bone, is adequate, supporting its use in dermatologic and musculoskeletal infections.

Metabolism

Limited hepatic metabolism occurs via conjugation with glucuronic acid, but the majority of cephalexin is excreted unchanged. Consequently, renal function largely dictates drug clearance.

Excretion

Renal clearance is approximately 1.5–2.0 L/h in healthy adults. The elimination half‑life (t_1/2) is about 1–2 hours in patients with normal renal function. In patients with impaired renal clearance, t_1/2 can extend to 4–6 hours or longer, necessitating dosage adjustment.

Mathematical Relationships

The relationship between dose, clearance, and area under the concentration‑time curve (AUC) follows:

AUC = Dose ÷ Clearance

Plasma concentration at any time t can be described by first‑order kinetics:

C(t) = C₀ × e⁻ᵏᵗ, where k = ln(2) ÷ t_1/2

For a multiple‑dose regimen achieving steady state, the peak and trough concentrations can be approximated by:

C_max = (Dose ÷ (CL × τ)) × (1 ÷ (1 – e⁻ᵏτ))

C_min = C_max × e⁻ᵏτ

where τ is the dosing interval.

Factors Affecting Pharmacokinetics

• Renal Function – Primary determinant of clearance; dose adjustment required in chronic kidney disease (CKD) stages 3–5.
• Age – Pediatric patients exhibit higher clearance rates; adult elderly may have reduced renal function.
• Drug Interactions – Oral contraceptives may reduce cephalexin plasma levels via increased intestinal metabolism; concurrent use of nephrotoxic agents may necessitate monitoring.
• Food Intake – Food does not significantly alter bioavailability, but high-fat meals may delay absorption slightly.

Clinical Significance

Therapeutic Indications

Cephalexin is indicated for the treatment of infections caused by susceptible Gram‑positive cocci, including:

• Skin and soft tissue infections (cellulitis, abscesses, impetigo)
• Otitis media and sinusitis in children
• Urinary tract infections (UTIs) caused by Escherichia coli and Klebsiella species
• Prophylaxis of surgical site infections in orthopedic procedures
• Acute bacterial sinusitis in patients with penicillin allergy

Clinical Applications

Cephalexin’s oral bioavailability and favorable safety profile make it suitable for outpatient management. The drug’s predictable pharmacokinetics enable dosing regimens that are easy to follow, reducing the risk of non‑compliance. In settings where broad‑spectrum coverage is unnecessary, cephalexin can serve as a narrow‑spectrum alternative, thereby mitigating the risk of antimicrobial resistance.

Adverse Effects and Tolerability

Common adverse reactions include gastrointestinal disturbances (nausea, vomiting, diarrhea) and hypersensitivity reactions (rash, urticaria). Severe allergic reactions are rare but may manifest as anaphylaxis. Hematologic effects such as neutropenia or thrombocytopenia have been reported in a minority of patients. Monitoring is recommended in patients with a history of hypersensitivity to β‑lactams.

Drug Interactions

Cephalexin is generally free from significant drug–drug interactions. However, concurrent use with oral contraceptives may reduce drug exposure; therefore, increased dosing may be considered. Probenecid can decrease renal clearance of cephalexin, potentially increasing plasma concentrations. Caution is advised when combining with nephrotoxic agents such as aminoglycosides or NSAIDs.

Safety in Special Populations

• Pediatrics – Dosage is weight‑based; typical dose is 25–50 mg/kg/day divided q8h or q6h.
• Renal Impairment – Dose reduction or extended dosing intervals are required; for patients with creatinine clearance <30 mL/min, dosing interval may be extended to q12h.
• Pregnancy – Category B; limited data suggest no teratogenic risk; however, caution is advised.
• Lactation – Minimal transfer into breast milk; considered safe for nursing mothers.

Clinical Applications/Examples

Case Scenario 1: Pediatric Cellulitis

A 5‑year‑old boy presents with erythema and swelling of the lower leg. Culture identifies Staphylococcus aureus susceptible to cephalexin (MIC 0.5 mg/L). A weight‑based dose of 50 mg/kg/day divided q8h (approximately 250 mg q8h) is prescribed. For a 25‑kg child, the total daily dose would be 1250 mg. The clinician aims to maintain C_max above the MIC for at least 60% of the dosing interval, which is achieved with q8h dosing given the drug’s t_1/2 of ~1.5 h. Treatment proceeds for 7 days, with clinical improvement noted after 48 hours. No adverse events reported.

Case Scenario 2: Chronic Kidney Disease – Stage 3

A 68‑year‑old woman with CKD stage 3 (creatinine clearance 45 mL/min) is diagnosed with a urinary tract infection due to Klebsiella pneumoniae (MIC 1 mg/L). Standard dosing would be 500 mg q12h. However, given reduced renal clearance, the dosing interval is extended to q24h, resulting in a dose of 500 mg once daily. The AUC is maintained within therapeutic range while minimizing accumulation. Follow‑up cultures show eradication of the organism, and the patient tolerates therapy well.

Case Scenario 3: Post‑operative Prophylaxis

An elective total knee arthroplasty patient receives pre‑operative cephalexin 2 g IV. Post‑operatively, the patient is transitioned to oral cephalexin 500 mg q8h for 24–48 hours. The regimen targets common skin flora such as Staphylococcus aureus and streptococci. The patient experiences no surgical site infection, and the therapy is discontinued after 48 hours in accordance with institutional guidelines.

Problem‑Solving Approach for Drug‑Interaction Concerns

1. Identify potential interacting agents (e.g., oral contraceptives, probenecid, NSAIDs).
2. Evaluate the mechanism of interaction (e.g., altered renal clearance, metabolic induction).
3. Adjust dosing accordingly (increase dose, extend interval, or substitute an alternative agent).
4. Monitor serum drug levels if feasible, or clinical response and adverse events.

Summary/Key Points

• Cephalexin is a first‑generation cephalosporin with time‑dependent bactericidal activity primarily against Gram‑positive cocci.
• Oral bioavailability is high (~90%), and the drug is predominantly renally excreted unchanged.
• Pharmacokinetic parameters such as t_1/2 (~1–2 h) and clearance determine dosing intervals; adjustments are essential in renal impairment.
• Typical therapeutic regimens include 250–500 mg q8h for adults and weight‑based dosing for pediatrics.
• Cephalexin’s narrow spectrum, low cost, and favorable safety profile make it an appropriate first‑line agent for uncomplicated skin, soft tissue, and urinary tract infections.
• Adverse effects are generally mild; serious hypersensitivity reactions require prompt recognition and discontinuation.
• Drug interactions are uncommon but may involve reduced plasma levels with oral contraceptives and increased exposure with probenecid.
• Clinical decision making should incorporate MIC values, patient renal function, and infection severity to optimize outcomes.

References

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2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
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8. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.