Cephalexin (Keflex)
cephalexin monohydrate
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Respiratory tract infections (S. pneumoniae, S. pyogenes) | Adults & pediatric ≥1 year | Monotherapy | FDA Approved |
| Otitis media (S. pneumoniae, H. influenzae, S. aureus, S. pyogenes, M. catarrhalis) | Adults & pediatric ≥1 year | Monotherapy | FDA Approved |
| Skin & skin structure infections (S. aureus [MSSA], S. pyogenes) | Adults & pediatric ≥1 year | Monotherapy | FDA Approved |
| Bone infections (S. aureus, P. mirabilis) | Adults & pediatric ≥1 year | Monotherapy or step-down | FDA Approved |
| Genitourinary tract infections including acute prostatitis (E. coli, P. mirabilis, K. pneumoniae) | Adults & pediatric ≥1 year | Monotherapy | FDA Approved |
Cephalexin is a workhorse oral antibiotic with strong activity against gram-positive cocci (MSSA, streptococci) and selected gram-negative bacilli (E. coli, K. pneumoniae, P. mirabilis). It has no activity against MRSA, enterococci, Pseudomonas, or Acinetobacter. First-generation cephalosporins remain the preferred oral step-down from IV cefazolin for MSSA infections including osteomyelitis and septic arthritis, and cephalexin is one of the most commonly prescribed antibiotics in the United States.
Infective endocarditis prophylaxis: AHA recommends cephalexin 2 g orally (adults) or 50 mg/kg (pediatric) as a single dose 30–60 minutes before dental procedures in penicillin-allergic patients (non-immediate hypersensitivity) with high-risk cardiac conditions. Evidence quality: High (AHA 2007 guideline).
Streptococcal pharyngitis (alternative): IDSA recommends a 10-day course of a first-generation cephalosporin (cephalexin 20 mg/kg BID, max 500 mg/dose) in penicillin-allergic patients without immediate-type hypersensitivity. Evidence quality: High.
Chronic suppressive therapy for prosthetic joint infections: IDSA recommends cephalexin 500 mg TID–QID as the preferred oral agent for chronic suppression of oxacillin-susceptible staphylococcal prosthetic joint infections. Evidence quality: Moderate.
Step-down from IV cefazolin (MSSA bacteremia, osteomyelitis): Commonly used as sequential oral therapy following initial IV cefazolin in pediatric and adult bone/joint infections. Evidence quality: High (PIDS/IDSA guidelines).
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Uncomplicated cellulitis / impetigo (MSSA / GAS) | 500 mg QID | 500 mg QID | 4 g/day | 7–14 days; IDSA SSTI guideline recommendation Impetigo may use 250 mg QID |
| Uncomplicated UTI | 250 mg Q6H | 500 mg Q12H | 4 g/day | 7–14 days; verify local E. coli susceptibility 500 mg BID shown equivalent to QID in ED study |
| Streptococcal pharyngitis (alternative to penicillin) | 500 mg BID | 500 mg BID | 1 g/day | 10 days minimum for GAS; IDSA guideline Pediatric: 20 mg/kg BID (max 500 mg/dose) |
| Otitis media | 250 mg Q6H | 250 mg Q6H | 4 g/day | 7–14 days Pediatric: 75–100 mg/kg/day in divided doses Q6H |
| Bone / joint infection — oral step-down | 500 mg QID | 500 mg QID | 4 g/day | Total duration per clinical response; step-down from IV cefazolin Higher doses (1 g QID) may be used in severe infections |
| Endocarditis prophylaxis (penicillin-allergic, non-immediate) | 2 g single dose | N/A | 2 g | 30–60 min before dental procedure AHA 2007; pediatric: 50 mg/kg (max 2 g) |
| Chronic suppression — prosthetic joint (MSSA) | 500 mg TID–QID | 500 mg TID–QID | 2 g/day | Indefinite; IDSA PJI guideline Preferred for oxacillin-susceptible staphylococci |
Renal Dose Adjustment (Adults & Pediatric ≥15 years)
| CrCl (mL/min) | Dosage Recommendation | Maximum Daily Dose | Notes | Source |
|---|---|---|---|---|
| ≥60 | No adjustment | 4 g | Standard dosing | FDA PI |
| 30–59 | No adjustment | 1 g/day | Cap maximum at 1 g/day | FDA PI |
| 15–29 | 250 mg Q8–12H | 750 mg | Monitor renal function | FDA PI |
| 5–14 (not on dialysis) | 250 mg Q24H | 250 mg | Single daily dose | FDA PI |
| 1–4 (not on dialysis) | 250 mg Q48–60H | 250 mg | Extended interval dosing | FDA PI |
Cephalexin’s short half-life (~1 hour) traditionally mandated QID dosing for time-dependent killing. However, BID dosing (500 mg every 12 hours) is now endorsed for uncomplicated infections by the FDA PI and has demonstrated equivalent efficacy for UTIs in a published emergency department study. For serious infections such as osteomyelitis or deep-seated MSSA infections, QID dosing with higher total daily doses (up to 4 g) is preferred to maximise the time above MIC. The drug can be taken with or without food and absorption is not significantly affected by meals.
Pharmacology
Mechanism of Action
Cephalexin is a bactericidal beta-lactam antibiotic that disrupts bacterial cell wall synthesis. It binds irreversibly to penicillin-binding proteins (PBPs), enzymes that catalyse the final transpeptidation step in peptidoglycan cross-linking. By blocking this essential reaction, cephalexin weakens the cell wall, rendering the bacterium vulnerable to osmotic pressure and ultimately resulting in cell lysis and death. The bactericidal effect is time-dependent, meaning clinical efficacy correlates with the proportion of the dosing interval during which free drug concentrations exceed the pathogen’s MIC (% fT > MIC). As a first-generation cephalosporin, cephalexin has excellent activity against gram-positive cocci including MSSA and streptococci, with more modest activity against selected gram-negative organisms. It is inherently inactive against MRSA due to the altered PBP2a target, and has no clinically useful activity against enterococci, Pseudomonas, or anaerobes.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | ~90% bioavailability; Tmax ~1 h; Cmax 9, 18, 32 mcg/mL at 250, 500, 1000 mg doses respectively | Rapid and nearly complete oral absorption; acid stable; food does not significantly affect total absorption |
| Distribution | Vd ~0.23 L/kg; 10–15% protein bound; distributes to kidney, liver, bone, respiratory tract | Low protein binding allows high free drug concentrations; good penetration into bone supports use in osteomyelitis step-down therapy |
| Metabolism | No detectable hepatic metabolism; does not affect CYP450 enzymes | Very low drug-drug interaction potential; no hepatic dose adjustment needed |
| Elimination | t½ 0.5–1.2 h; >90% excreted unchanged in urine within 8 h via glomerular filtration and tubular secretion; peak urine concentrations ~1000–5000 mcg/mL | Very high urinary concentrations support efficacy in UTIs; short half-life requires multiple daily dosing; dose reduction needed when CrCl <30 mL/min |
Side Effects
The FDA prescribing information for cephalexin does not report specific percentage incidence rates for individual adverse reactions from pivotal trials. It lists reactions descriptively as “most frequent” or “have been reported.” The incidence estimates below are derived from published clinical literature and systematic reviews, supplemented by class-effect data from first-generation cephalosporin studies.
| Adverse Effect | Estimated Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 2–5% | Most frequently reported adverse reaction (FDA PI); distinguish from C. difficile if persistent or bloody |
| Nausea | 1–3% | Usually self-limiting; taking with food may reduce GI intolerance |
| Dyspepsia / abdominal pain | 1–3% | Grouped in FDA PI with nausea; resolves on completion of therapy |
| Vomiting | 1–2% | More common in pediatric patients; ensure adequate hydration |
| Adverse Effect | Estimated Incidence | Clinical Note |
|---|---|---|
| Vaginal candidiasis / genital pruritus | <2% | Class effect from disruption of normal flora; advise patients about symptoms |
| Dizziness / headache | <2% | Rarely treatment-limiting |
| Fatigue | <1% | May reflect underlying infection rather than drug effect |
| Rash / urticaria | <2% | Evaluate for hypersensitivity; discontinue if progressive |
| Elevated AST/ALT | <1% | Slight, transient elevations reported; usually not clinically significant |
| Eosinophilia | <1% | Typically transient; may reflect drug hypersensitivity |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylaxis / severe hypersensitivity | Rare (<0.1%) | Minutes to hours after first dose | Discontinue immediately; epinephrine; emergency care; do not rechallenge |
| Stevens-Johnson syndrome / TEN | Very rare | 1–3 weeks | Discontinue immediately; dermatology referral; supportive care |
| Clostridioides difficile-associated diarrhea | Uncommon | During or up to 2 months post-therapy | Test for C. difficile toxin; discontinue cephalexin; treat with vancomycin or fidaxomicin |
| Drug-induced hemolytic anemia (positive Coombs’ test) | Rare | During therapy | Discontinue; evaluate with direct Coombs’ test and hemolysis workup; transfuse if needed |
| Seizures | Rare (primarily with renal impairment) | Variable; risk increases with accumulation | Discontinue; anticonvulsant therapy if needed; dose-adjust for renal function |
| Interstitial nephritis | Very rare | Days to weeks | Discontinue; evaluate renal function; usually reversible |
| Neutropenia / thrombocytopenia | Rare | Prolonged therapy (>2 weeks) | Monitor CBC if therapy exceeds 14 days; discontinue if significant cytopenias develop |
Cross-hypersensitivity between penicillins and cephalosporins occurs in up to 10% of patients with a documented penicillin allergy (FDA PI). This rate is higher for first-generation cephalosporins due to structural R1 side-chain similarity with aminopenicillins. Cephalexin shares an identical R1 side chain with ampicillin/amoxicillin, which is a key determinant of allergic cross-reactivity. Patients with a confirmed immediate-type (IgE-mediated) reaction to amoxicillin or ampicillin should not receive cephalexin. In patients with non-immediate penicillin allergy (e.g., delayed rash), cephalexin can generally be used with appropriate monitoring.
Drug Interactions
Cephalexin undergoes no hepatic metabolism and does not affect CYP450 enzymes, giving it a very favourable drug interaction profile. The two clinically relevant interactions involve altered renal excretion (probenecid) and competition for renal tubular transport (metformin).
Monitoring
-
Renal Function
Baseline; periodically in at-risk patients
Routine Assess CrCl before initiating therapy, particularly in elderly patients. Dose adjustment required when CrCl falls below 30 mL/min. Monitor during therapy if renal impairment is present or develops. -
Clinical Response
48–72 h after starting therapy
Routine Evaluate for clinical improvement. Consider alternative antibiotics or broader coverage if no response within 48–72 hours. Obtain cultures if not already done. -
GI Symptoms / Stool
If diarrhea develops
Trigger-based Test for C. difficile toxin if diarrhea is persistent, watery, or bloody, or if it develops during or up to 2 months after therapy. -
CBC
If therapy exceeds 14 days
Trigger-based Monitor for neutropenia, thrombocytopenia, and eosinophilia during prolonged courses (e.g., osteomyelitis, chronic suppression). -
Blood Glucose
During concurrent metformin use
Trigger-based Cephalexin increases metformin concentrations. Monitor glucose closely in diabetic patients and adjust metformin dose if needed. -
PT/INR
If on anticoagulants
Trigger-based Monitor prothrombin time in patients on warfarin, especially those with renal or hepatic impairment, poor nutritional status, or receiving prolonged therapy.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to cephalexin or any member of the cephalosporin class of antibacterial drugs
Relative Contraindications (Specialist Input Recommended)
- Immediate-type (IgE-mediated) penicillin allergy (anaphylaxis, urticaria, angioedema) — cross-hypersensitivity may occur in up to 10% of penicillin-allergic patients; risk is higher with cephalexin specifically due to shared R1 side chain with aminopenicillins
- MRSA infection — cephalexin has no activity against methicillin-resistant staphylococci; confirm susceptibility before initiating empiric therapy
Use with Caution
- Renal impairment (CrCl <30 mL/min) — dose reduction required; risk of drug accumulation, seizures, and prolonged toxicity
- Elderly patients — more likely to have impaired renal function; verify CrCl before dosing
- History of GI disease, particularly colitis — increased susceptibility to C. difficile-associated diarrhea
- Concurrent anticoagulant therapy — cephalosporins may prolong PT; monitor in patients with renal/hepatic impairment or poor nutritional status
- Patients under 1 year of age — safety and effectiveness not established in this age group
Cross-hypersensitivity among beta-lactam antibacterial drugs may occur in up to 10% of patients with a history of penicillin allergy. Before therapy with cephalexin is initiated, clinicians should inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. If an allergic reaction to cephalexin occurs, the drug should be discontinued immediately and appropriate treatment should be instituted (FDA PI, revised March 2026).
Patient Counselling
Purpose of Therapy
Cephalexin is a prescription antibiotic used to treat bacterial infections of the skin, bones, ears, respiratory tract, and urinary tract. It works by weakening and destroying the walls of bacteria. It is effective only against bacterial infections and will not treat viral illnesses such as the common cold or flu.
How to Take
Take cephalexin exactly as prescribed, typically every 6 or 12 hours depending on the infection. It may be taken with or without food; taking it with a meal or snack can help reduce stomach upset. Complete the full course of treatment even if you feel better, as stopping early may allow bacteria to survive and become resistant. Shake the liquid suspension well before each use, and keep it refrigerated (discard after 14 days).
Sources
- Keflex (cephalexin) for oral suspension prescribing information. Pragma Pharmaceuticals, LLC. Revised March 2026. FDA Label Primary source for all approved indications, dosing (including renal adjustment table), adverse reactions, drug interactions, and PK data cited in this monograph.
- Keflex (cephalexin) capsules prescribing information. Revised 2019. FDA Label Capsule formulation label with identical PK parameters and clinical information; confirms 250/500/750 mg capsule availability.
- Kanan M, Atif S, Mohammed F, et al. A systematic review on the clinical pharmacokinetics of cephalexin in healthy and diseased populations. Antibiotics. 2023;12(9):1402. doi:10.3390/antibiotics12091402 Comprehensive PK systematic review confirming bioavailability (~90%), Vd (0.23 L/kg), half-life (0.5–1.2 h), and renal clearance parameters.
- Haynes AS, Wei Z, Anderson P, Scheetz MH, Parker SK, Fish DN. Cefadroxil and cephalexin pharmacokinetics and pharmacodynamics in children with musculoskeletal infections. Antimicrob Agents Chemother. 2024;68(5):e00182-24. doi:10.1128/aac.00182-24 Population PK study in pediatric bone/joint infections; provides Monte Carlo simulations for dosing optimisation and confirms 15% protein binding.
- Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the IDSA. Clin Infect Dis. 2014;59(2):e10-e52. doi:10.1093/cid/ciu296 IDSA guideline recommending cephalexin 500 mg QID for nonpurulent cellulitis and 250 mg QID for impetigo.
- Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the IDSA. Clin Infect Dis. 2012;55(10):e86-e102. doi:10.1093/cid/cis629 IDSA guideline recommending first-generation cephalosporins as alternative to penicillin for GAS pharyngitis in non-immediate penicillin-allergic patients.
- Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association. Circulation. 2007;116(15):1736-1754. doi:10.1161/CIRCULATIONAHA.106.183095 AHA guideline recommending cephalexin 2 g as single-dose endocarditis prophylaxis for penicillin-allergic patients without immediate-type hypersensitivity.
- Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the IDSA. Clin Infect Dis. 2013;56(1):e1-e25. doi:10.1093/cid/cis803 IDSA PJI guideline recommending cephalexin as preferred oral agent for chronic suppression of oxacillin-susceptible staphylococcal prosthetic joint infections.
- Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the PIDS and the IDSA. Clin Infect Dis. 2011;53(7):e25-e76. doi:10.1093/cid/cir531 PIDS/IDSA guideline recommending cephalexin as preferred step-down for community-acquired pneumonia caused by MSSA in children.
- Tipper DJ. Mode of action of beta-lactam antibiotics. Pharmacol Ther. 1985;27(1):1-35. doi:10.1016/0163-7258(85)90062-2 Foundational review of beta-lactam mechanism of action through PBP binding and cell wall synthesis inhibition.
- Regamey C, Steinberg E, Kirby WMM. Pharmacokinetics of parenteral sodium cephalexin in comparison with cephalothin and cefazolin. Infection. 1977;5(3):173-180. doi:10.1007/BF01642232 Classic PK study confirming cephalexin half-life (0.9 h), renal clearance (252 mL/min/1.73 m²), and the effect of probenecid on half-life prolongation.
- Nightingale CH, Greene DS, Quintiliani R. Pharmacokinetics and clinical use of cephalosporin antibiotics. J Pharm Sci. 1975;64(12):1899-1926. doi:10.1002/jps.2600641203 Comprehensive review of cephalosporin PK including cephalexin; confirms protein binding (10–15%), urinary excretion (>90%), and tissue distribution.