CEPHALEXIN

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-All dosage forms may be administered without regard to meals.

Oral Solid Formulations
-Capsules and Tablets: Swallow whole. May be taken without regard to meals.

Oral Liquid Formulations
-Cephalexin oral suspension may be taken without regard to meals.
-Shake well prior to each use.
-To ensure accurate dosage, measure dose with a calibrated oral syringe, spoon, or measuring cup.

Suspension reconstitution
-Review the manufacturer's reconstitution instructions for the particular product and package size as the amount of water used for reconstitution may vary between manufacturers.
-Follow the manufacturer's directions for mixing; the water volume is usually added in 2 aliquots, shaking well after each addition.
-Storage: After mixing, store under refrigeration for up to 14 days.

Gastrointestinal adverse reactions (nausea, vomiting, diarrhea) are some of the most common adverse reactions to cephalexin and occur in < 5% of patients receiving cephalexin in the general population. Other gastrointestinal effects include abdominal pain, gastritis, and dyspepsia. Colitis has been reported with the cephalosporin class.

Allergic reactions (i.e., rash, angioedema, and urticaria) have been observed with cephalexin. Erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported rarely. Approximately 1% to 3% of treatment courses in the general population result in some kind of dermatologic allergic reaction. These reactions usually resolve upon discontinuation of the drug. Anaphylaxis or anaphylactoid reactions have also been reported and are likely to occur in 0.0001% to 0.1% of patients.

Cephalexin has been associated with acute generalized exanthematous pustulosis (AGEP). The non-follicular, pustular, erythematous rash starts suddenly and is associated with fever above 38 degrees C. Drugs are the main cause of AGEP. A period of 2-3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days.

Nephrotoxicity occurs very rarely during therapy with cephalexin, but patients with renal dysfunction and patients receiving other nephrotoxic drugs may be more susceptible. Interstitial nephritis, a hypersensitivity reaction, has been reported with many of the cephalosporins, including rarely (< 1%) with cephalexin. Renal dysfunction, increased BUN and creatinine (i.e., azotemia), and toxic nephropathy have been reported with the cephalosporin class.

Seizures are a rare (< 1%), but serious, complication of cephalosporin therapy. More commonly associated with penicillins, the epileptogenic properties of both penicillins and cephalosporins are thought to be related to their beta-lactam ring. High doses and administration to patients with renal impairment (without an appropriate dosage reduction) are associated with an increased risk of seizures. Discontinue the drug if seizures occur; if clinically indicated, anticonvulsant therapy can be used.

Eosinophilia, neutropenia, thrombocytopenia, acute intravascular hemolysis, and hemolytic anemia have been reported in patients receiving cephalexin. Agranulocytosis, aplastic anemia, hemorrhage (bleeding), leukopenia, pancytopenia, and prolonged prothrombin time (hypoprothrombinemia) have been reported with cephalosporin-class antibiotics. Positive direct Coombs' tests have been reported in patients receiving cephalosporins. If hematological testing is performed in patients receiving cephalosporins, a positive Coombs' test should be considered as being possibly due to the antibiotic.

As with other cephalosporins, a transient rise in AST and ALT (elevated hepatic enzymes) concentrations has been observed with patients receiving cephalexin. Elevated transaminases have been noted in 1-7% of patients in the general population receiving cephalosporins. Other adverse events associated with the cephalosporin class include hepatic dysfunction (including transient hepatitis, cholestasis, and jaundice), hyperbilirubinemia, and elevated alkaline phosphatase and LDH.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with cephalexin. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Other adverse reactions reported with cephalexin include genital and anal pruritus (pruritus ani) as well as local candidiasis such as thrush, genital moniliasis, and symptoms of vaginitis and vaginal discharge.

Generalized adverse events associated with cephalexin include dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis, and joint disorder. Fever has been reported with cephalosporin-class antibiotics.

A false-positive reaction for glucose in the urine has been observed in patients receiving cephalosporins and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, Diastix). Patients with diabetes mellitus who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on cephalexin treatment.

A positive direct Coombs test may develop in some patients receiving cephalosporins. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' testing of newborns whose mothers received cephalexin before delivery, clinicians should keep in mind that a positive Coombs' test may be due to the drug.

Cephalexin is contraindicated in patients with cephalosporin hypersensitivity or cephamycin hypersensitivity. Cephalexin should be used cautiously in patients with hypersensitivity to penicillin. The structural similarity between cephalexin and penicillin causes these patients to be more susceptible to hypersensitivity reactions. Penicillins can cause a variety of hypersensitivity reactions ranging from mild rash to fatal anaphylaxis. Patients who have experienced severe penicillin hypersensitivity should not receive cephalexin. While the FDA-approved product label states that cross-hypersensitivity among beta-lactam antibiotics may occur in up to 10% of patients with a history of penicillin allergy, other experts report an incidence of cross-reactivity of approximately 3 to 7% of patients with a documented history to penicillin.

Because cephalexin is renally eliminated, use it with caution in patients with significant renal disease, renal impairment (CrCl < 30 mL/min, with or without dialysis) or renal failure. The degree of renal impairment and the severity of the infection will determine whether dose or dosing interval adjustments are required. Careful clinical observation and renal function monitoring should be conducted in these patients. Rarely, cephalexin may worsen renal function; pre-existing renal impairment may increase the risk of drug-induced renal toxicity.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including cephalexin, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

All cephalosporins, including cephalexin, may rarely cause hypothrombinemia and have the potential to cause bleeding. Cephalosporins that contain the NMTT side chain (e.g., cefoperazone, cefamandole, cefotetan) have been associated with an increased risk for bleeding. Those at risk include patients with renal or hepatic impairment, patients with poor nutritional status, patients receiving a prolonged course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in at risk patients with a preexisting coagulopathy (e.g., vitamin K deficiency) because these patients are at a higher risk for developing bleeding complications; exogenous vitamin K should be administered as indicated.

Description: Cephalexin is an oral, first-generation cephalosporin antibiotic with activity against most gram-positive bacteria. Cephalexin is used primarily in children for the treatment of infections of the respiratory tract (e.g., pharyngitis, tonsillitis), skin infections, bone and joint infections, and urinary tract infections caused by susceptible staphylococci, Streptococcus pneumoniae, and group A beta-hemolytic streptococci. Cephalexin is considered one of the recommended agents for group A streptococcal (GAS) pharyngitis in patients with penicillin allergy. Cephalexin is FDA-approved for use in pediatric patients older than 1 year of age.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Escherichia coli, Haemophilus influenzae (beta-lactamase negative), Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Streptococcus agalactiae (group B streptococci)
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of skin and skin structure infections, including impetigo, cellulitis, erysipelas, skin abscesses, furunculosis, and carbuncle:
-for the treatment of unspecified skin and skin structure infections:
Oral dosage:
Infants*, Children, and Adolescents: 25 to 50 mg/kg/day PO in 2 to 4 divided doses for 7 to 14 days. Up to 100 mg/kg/day (Max: 4 g/day) may be used.
-for the treatment of impetigo:
Oral dosage:
Infants*, Children, and Adolescents: 25 to 50 mg/kg/day PO in 2 to 4 divided doses (Max: 1 g/day) for 5 to 7 days.
-for the treatment of nonpurulent skin infections, such as cellulitis and erysipelas:
Oral dosage:
Infants*, Children, and Adolescents: 25 to 50 mg/kg/day PO in 4 divided doses (Max: 2 g/day) for 5 to 14 days.
-for the treatment of purulent skin infections, such as furunculosis, carbuncle, and skin abscesses:
Oral dosage:
Infants*, Children, and Adolescents: 25 to 50 mg/kg/day PO in 4 divided doses (Max: 2 g/day) for 5 to 10 days plus incision and drainage.

For the treatment of upper respiratory tract infections, including group A beta-hemolytic streptococcal (GAS) pharyngitis (primary rheumatic fever prophylaxis) and tonsillitis:
-for the treatment of nonspecific upper respiratory tract infections:
Oral dosage:
Infants*, Children, and Adolescents: 25 to 50 mg/kg/day PO in 2 to 4 divided doses for 7 to 14 days. Up to 100 mg/kg/day (Max: 4 g/day) may be used.
-for the treatment of group A beta-hemolytic streptococcal (GAS) pharyngitis (primary rheumatic fever prophylaxis) and tonsillitis:
Oral dosage:
Infants*, Children, and Adolescents: 20 mg/kg/dose (Max: 500 mg/dose) PO every 12 hours for 10 days as an alternative in patients allergic to penicillin.

For the treatment of lower respiratory tract infections (LRTIs), including community-acquired pneumonia (CAP):
-for the treatment of nonspecific lower respiratory tract infections (LRTIs):
Oral dosage:
Infants*, Children, and Adolescents: 25 to 50 mg/kg/day PO divided in 2 to 4 doses (Max: 2 g/day) for mild to moderate infections or 50 to 100 mg/kg/day PO divided in 3 to 4 doses (Max: 4 g/day) for severe infections.
-for the treatment of community-acquired pneumonia (CAP):
Oral dosage:
Infants 4 to 11 months*, Children, and Adolescents: 75 to 100 mg/kg/day PO divided in 3 or 4 doses (Max: 4 g/day) for 10 days. Guidelines recommend cephalexin as initial therapy for mild infections or oral step-down therapy for infections due to methicillin-sensitive S. aureus (MSSA).

For the treatment of bone and joint infections, including osteomyelitis, infectious arthritis*, and infectious bursitis*:
-for the treatment of osteomyelitis including as step-down therapy after initial IV therapy:
Oral dosage:
Infants 1 to 2 months*: 75 to 150 mg/kg/day PO in 3 to 4 divided doses. Treat for a total duration of 4 to 6 weeks (parenteral plus oral). A longer course (several months) may be needed for severe or complicated infections.
Infants 3 to 11 months*: 75 to 150 mg/kg/day PO in 3 to 4 divided doses. Treat for a total duration of 3 to 4 weeks (parenteral plus oral) for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for severe or complicated infections.
Children and Adolescents: 75 to 150 mg/kg/day (Max: 6 g/day) PO in 3 to 4 divided doses. Treat for a total duration of 3 to 4 weeks (parenteral plus oral) for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for severe or complicated infections.
-for step-down therapy for infectious arthritis* after initial IV therapy:
Oral dosage:
Infants 1 to 2 months: 75 to 150 mg/kg/day PO in 3 to 4 divided doses. Treat for a total duration of 4 to 6 weeks (parenteral plus oral). A longer course (several months) may be needed for severe or complicated infections.
Infants 3 to 11 months: 75 to 150 mg/kg/day PO in 3 to 4 divided doses. Treat for a total duration of 2 to 3 weeks (parenteral plus oral) for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for septic hip arthritis or severe or complicated infections.
Children and Adolescents: 75 to 150 mg/kg/day (Max: 6 g/day) PO in 3 to 4 divided doses. Treat for a total duration of 2 to 3 weeks (parenteral plus oral) for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for septic hip arthritis or severe or complicated infections.
-for the treatment of infectious bursitis*:
Oral dosage:
Children and Adolescents: 75 to 150 mg/kg/day (Max: 6 g/day) PO in 3 to 4 divided doses for 2 to 3 weeks. Generally, 2 weeks is appropriate for most patients; immunocompromised patients may require a longer duration.

For the treatment of urinary tract infection (UTI), including cystitis, prostatitis, pyelonephritis, and catheter-associated urinary tract infection:
-for the treatment of nonspecific UTI:
Oral dosage:
Children 1 to 2 years: 50 to 100 mg/kg/day PO in 4 divided doses for 7 to 14 days. The FDA-approved dosage is 25 to 50 mg/kg/day PO in 2 to 4 divided doses. For severe infections, 50 to 100 mg/kg/day PO in 3 to 4 divided doses may be used.
Children and Adolescents 3 to 17 years: 25 to 50 mg/kg/day (Max: 2 g/day) PO in 2 to 4 divided doses. For severe infections, 50 to 100 mg/kg/day (Max: 4 g/day) PO in 3 to 4 divided doses may be used. Treat for 7 to 14 days.
-for the treatment of acute uncomplicated lower UTI:
Oral dosage:
Infants 2 to 11 months*: 50 to 100 mg/kg/day PO in 4 divided doses for 3 to 5 days.
Children 1 to 2 years: 50 to 100 mg/kg/day PO in 4 divided doses for 3 to 5 days.
Children and Adolescents 3 to 17 years: 25 to 50 mg/kg/day (Max: 2 g/day) PO in 2 to 4 divided doses for 3 to 5 days.
-for the treatment of severe UTI, including pyelonephritis:
Oral dosage:
Infants 2 to 11 months*: 50 to 100 mg/kg/day PO in 4 divided doses for 7 to 14 days.
Children 1 to 11 years: 50 to 100 mg/kg/day (Max: 4 g/day) PO in 3 to 4 divided doses for 7 to 14 days.
Children and Adolescents 12 to 17 years: 50 to 100 mg/kg/day (Max: 6 g/day) PO in 3 to 4 divided doses for 7 to 14 days.
-for the treatment of catheter-associated UTI:
Oral dosage:
Infants 2 to 11 months*: 50 to 100 mg/kg/day PO in 4 divided doses for 7 to 14 days.
Children 1 to 11 years: 50 to 100 mg/kg/day (Max: 4 g/day) PO in 3 to 4 divided doses for 7 to 14 days.
Children and Adolescents 12 to 17 years: 50 to 100 mg/kg/day (Max: 6 g/day) PO in 3 to 4 divided doses for 7 to 14 days.

For urinary tract infection (UTI) prophylaxis* in infants with hydronephrosis or vesicoureteral reflux:
NOTE: Routine antimicrobial prophylaxis for patients aged 2 to 24 months with vesicoureteral reflux is not supported by currently available data; however, antimicrobial prophylaxis is still utilized and has biological plausibility.
Oral dosage:
Neonates: 10 to 15 mg/kg/dose PO every 24 hours. Guidelines recommend antibiotic prophylaxis for all grades of vesicoureteral reflux in all children younger than 1 year.
Infants younger than 2 months: 10 to 15 mg/kg/dose PO every 24 hours. Guidelines recommend antibiotic prophylaxis for all grades of vesicoureteral reflux in all children younger than 1 year.

For bacterial endocarditis prophylaxis*:
Oral dosage:
Children and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) PO as a single dose given 30 to 60 minutes before procedure as an alternative for patients allergic to penicillin. Prophylaxis is recommended for at-risk cardiac patients who are undergoing dental procedures that involve manipulation of gingival tissue, manipulation of the periapical region of teeth, or perforation of the oral mucosa.

For the treatment of otitis media:
Oral dosage:
Children and Adolescents: 75 to 100 mg/kg/day PO in 3 to 4 divided doses (Max: 2 to 4 g/day). Although cephalexin is FDA-approved for the treatment of otitis media, it is not recommended as a treatment option in the guidelines by the American Academy of Pediatrics (AAP). Second- or third-generation oral cephalosporins (i.e., cefdinir, cefuroxime, and cefpodoxime) are the recommended agents for patients allergic to amoxicillin.

For the treatment of peritoneal dialysis catheter-related infection*:
Oral dosage:
Infants, Children, and Adolescents: 10 to 20 mg/kg/day PO divided every 12 to 24 hours (Max: 1 g/day) for at least 14 to 28 days.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 15 mg/kg/day PO have been used for UTI prophylaxis.
-Infants
100 mg/kg/day PO is FDA-approved maximum; however, doses up to 150 mg/kg/day PO have been used off-label.
-Children
100 mg/kg/day (Max: 4 g/day) PO is FDA-approved maximum; however, doses up to 150 mg/kg/day (Max: 6 g/day) PO have been used off-label.
-Adolescents
100 mg/kg/day (Max: 4 g/day) PO is FDA-approved maximum; however, doses up to 150 mg/kg/day (Max: 6 g/day) PO have been used off-label.

Patients with Hepatic Impairment Dosing
No dosage adjustments are necessary.

Patients with Renal Impairment Dosing
The following dosage adjustments are based on a usual dose in pediatric patients of 25 to 50 mg/kg/day PO divided every 6 hours :
CrCl > 50 mL/min/1.73 m2: No dosage adjustment needed.
CrCl 30 to 50 mL/min/1.73 m2: 5 to 10 mg/kg/dose PO every 8 hours.
CrCl 10 to 29 mL/min/1.73 m2: 5 to 10 mg/kg/dose PO every 12 hours.
CrCl < 10 mL/min/1.73 m2: 5 to 10 mg/kg/dose PO every 24 hours.

FDA-approved dosage adjustments (adolescents at least 15 years of age):
CrCl >= 60 mL/min: No dosage adjustment needed.
CrCl 30 to 59 mL/min: No dosage adjustments; maximum daily dose should not exceed 1 gram PO.
CrCl 15 to 29 mL/min: 250 mg PO every 8 hours or 12 hours.
CrCl 5 to 14 mL/min (not yet on dialysis): 250 mg PO every 24 hours.
CrCl 1 to 4 mL/min (not yet on dialysis): 250 mg PO every 48 hours or 60 hours.


Dialysis
NOTE: Although the FDA product label states there is insufficient information to make dosage adjustment recommendations in patients on hemodialysis, some experts recommend the following regimens:

Intermittent hemodialysis
5 to 10 mg/kg/dose PO every 24 hours, after hemodialysis.

Peritoneal dialysis
For mild infections: 5 to 10 mg/kg/dose PO every 24 hours.
For exit-site and tunnel infections: 10 to 20 mg/kg/day given in 1 or 2 doses (Max: 1000 mg/day).

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Cephalexin, a beta-lactam antibiotic similar to penicillins, inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinsic activity of cephalexin, as well as the other cephalosporins and penicillins, against a particular organism depends on its ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, cephalexin's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.

Beta-lactams, including cephalexin, exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism (free T above the MIC). This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase. Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval. The percentage of time required for both bacteriostatic and maximal bactericidal activity is different for the various classes of beta-lactams. Cephalosporins require free drug concentrations to be above the MIC for 35% to 40% of the dosing interval for bacteriostatic activity and 60% to 70% of the dosing interval for bactericidal activity.

Considering site of infection and appropriate cephalexin dosing, oxacillin-susceptible Staphylococcus sp. can be considered susceptible to cephalexin. Breakpoints for cefazolin are used to predict results for cephalexin for treatment of uncomplicated urinary tract infections due to E. coli, K. pneumoniae, and P. mirabilis.

Pharmacokinetics: Cephalexin is administered orally. Approximately 10 to 15% of the circulating drug is protein-bound. Cephalexin is distributed into most body tissues and fluids but does not reach therapeutic concentrations within the CSF or aqueous humour. Cephalexin is largely excreted unchanged (90%) in the urine via glomerular filtration and tubular secretion, which leads to high urinary concentrations. The elimination half-life is approximately 1 hour in adults with normal renal function.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Cephalexin is rapidly absorbed after oral administration. Peak concentrations are reached approximately 30-60 minutes after administration in infants and children. In a pharmacokinetic study in 20 infants and children, peak concentrations at 30 minutes were higher when cephalexin was given in the fasting state (23.4 mg/L) compared to the fed state (8.7 mg/L). However, the FDA-approved labeling states that cephalexin may be given without regard to meals.


-Special Populations
Pediatrics
Infants and Children
The elimination half-life of cephalexin in infants and children is approximately 1 hour, which is similar to the half-life in adults.

Renal Impairment
The pharmacokinetics of cephalexin in pediatric patients with renal impairment have not been extensively studied. However, cephalexin is primarily excreted by the kidneys and clearance is decreased in patients with renal impairment. In adults with renal impairment, the elimination half-life of cephalexin is prolonged to 4-6 hours in patients with a CrCl of 15-30 ml/min, 6-10 hours in patients with a CrCl of 5-15 ml/min, and 30-40 hours in patients with a CrCl < 5 ml/min. Cephalexin is moderately dialyzable (20-50%).