Cefditoren Pivoxil

Class: Third Generation Cephalosporins
Chemical Name: (+) - (6R,7R) - 7 - [2 - (2 - Amino - 4 - thiazolyl)glyoxylamido - 3 - [(Z) - 2 - (4 - methyl - 5 - thiazolyl)vinyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylic acid
Molecular Formula: C₁₉H₁₈N₆O₅S₃
CAS Number: 104145-95-1
Brands: Spectracef

Introduction

Antibacterial; β-lactam antibiotic; aminothiazolyl derivative third generation cephalosporin.^{2 3}

Uses for Cefditoren Pivoxil

Pharyngitis and Tonsillitis

Treatment of pharyngitis and tonsillitis caused by susceptible S. pyogenes (group A β-hemolytic streptococci).^{1 3} Generally effective in eradicating S. pyogenes from the nasopharynx, but efficacy in prevention of subsequent rheumatic fever has not been established to date.¹

CDC, AAP, IDSA, AHA, and others recommend oral penicillin V or IM penicillin G benzathine as treatments of choice;^{5 6 7 8} oral cephalosporins and oral macrolides considered alternatives.^{5 6 7 8} Amoxicillin sometimes used instead of penicillin V, especially for young children.^{6 7}

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Respiratory Tract Infections

Treatment of mild to moderate acute bacterial exacerbations of chronic bronchitis caused by susceptible Haemophilus influenzae (including β-lactamase-producing strains), H. parainfluenzae (including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including β-lactamase-producing strains).^{1 3}

Treatment of community-acquired pneumonia (CAP) caused by H. influenzae (including β-lactamase-producing strains), H. parainfluenzae (including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including β-lactamase-producing strains).¹

If an oral cephalosporin is used as an alternative to penicillin G or amoxicillin for treatment of CAP caused by penicillin-susceptible S. pneumoniae, ATS and IDSA recommend cefpodoxime, cefprozil, cefuroxime, cefdinir, or cefditoren.⁹

Skin and Skin Structure Infections

Treatment of uncomplicated skin and skin structure infections caused by susceptible Staphylococcus aureus (including β-lactamase-producing strains) or S. pyogenes.^{1 3}

Cefditoren Pivoxil Dosage and Administration

Administration

Oral Administration

Administer orally with meals (to enhance GI absorption).^{1 3}

Dosage

Available as cefditoren pivoxil; dosage expressed in terms of cefditoren.¹

Pediatric Patients

Pharyngitis and Tonsillitis

Oral

Children ≥12 years of age: 200 mg twice daily for 10 days.¹

Respiratory Tract Infections

Acute Bacterial Exacerbations of Chronic Bronchitis

Oral

Children ≥12 years of age: 400 mg twice daily for 10 days.¹

Community-acquired Pneumonia

Oral

Children ≥12 years of age: 400 mg twice daily for 14 days.¹

Skin and Skin Structure Infections

Oral

Children ≥12 years of age: 200 mg twice daily for 10 days.¹

Adults

Pharyngitis and Tonsillitis

Oral

200 mg twice daily for 10 days.¹

Respiratory Tract Infections

Acute Bacterial Exacerbations of Chronic Bronchitis

Oral

400 mg twice daily for 10 days.¹

Community-acquired Pneumonia

Oral

400 mg twice daily for 14 days.¹

Skin and Skin Structure Infections

Oral

200 mg twice daily for 10 days.¹

Special Populations

Hepatic Impairment

No dosage adjustments required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).¹

Pharmacokinetics have not been studied in patients with severe hepatic impairment (Child-Pugh class C).¹

Renal Impairment

No dosage adjustments required in patients with mild renal impairment (Cl_cr 50–80 mL/min per 1.73 m²).¹

Maximum dosage of 200 mg twice daily recommended for those with moderate renal impairment (Cl_cr 30–49 mL/min per 1.73 m²).¹

Maximum dosage of 200 mg once daily recommended for those with severe renal impairment (Cl_cr <30 mL/min per 1.73 m²).¹

The appropriate dosage for patients with end-stage renal disease has not been determined.¹

Geriatric Patients

No dosage adjustments except those related to renal impairment.^{1 3} Cautious dosage selection because of age-related decreases in renal function.¹ (See Renal Impairment under Dosage and Administration.)¹

Cautions for Cefditoren Pivoxil

Contraindications

• Known hypersensitivity to cefditoren, other cephalosporins, or any ingredient in the formulation.¹

• Carnitine deficiency or an inborn error of metabolism that may result in clinically important carnitine deficiency.¹

• Milk protein hypersensitivity (not lactose intolerance).¹

Warnings/Precautions

Warnings

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

Possible emergence and overgrowth of nonsusceptible bacteria or fungi with prolonged use.¹ Careful observation of the patient is essential.¹ Institute appropriate therapy if superinfection occurs.¹

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.¹ C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including cefditoren, and may range in severity from mild diarrhea to fatal colitis.^{1 a} Hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.^a

Consider CDAD if diarrhea develops during or after therapy and manage accordingly.¹ Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.^a

If CDAD is suspected or confirmed, the anti-infective may need to be discontinued.^a Some mild cases may respond to discontinuance alone.^{1 a} Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.^{1 a}

Sensitivity Reactions

Hypersensitivity Reactions

Possible hypersensitivity reactions such as urticaria, pruritus, rash (maculopapular, erythematous, morbilliform), fever and chills, eosinophilia, joint pain or inflammation, edema, erythema, genital and anal pruritus, angioedema, shock, hypotension, vasodilatation, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis, and anaphylaxis reported with cephalosporins.¹

If hypersensitivity reactions occur, discontinue cefditoren and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).¹

Cross-hypersensitivity

Partial cross-sensitivity among cephalosporins and other β-lactam antibiotics, including penicillins and cephamycins.¹

Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs.¹ Cautious use recommended in patients with a history of hypersensitivity to penicillins:¹ avoid use in those who have had an immediate-type (anaphylactic) hypersensitivity reaction ¹ and administer with caution in those who have had a delayed-type (e.g., rash, fever, eosinophilia) reaction.^a

Hypersensitivity to Milk Protein

Cefditoren tablets contain sodium caseinate, a milk protein, and should not be used in patients with milk protein hypersensitivity (not lactose intolerance).¹

General Precautions

Carnitine Deficiency

Cefditoren pivoxil should not be used when prolonged anti-infective therapy is required since use of other pivalate-containing compounds over periods of months have caused clinical manifestations of carnitine deficiency.¹

In individuals receiving short-term treatment with cefditoren pivoxil (200 or 400 mg of cefditoren twice daily for 14 days), a 30–63% decrease in serum carnitine concentrations has occurred; no adverse effects attributable to decreased carnitine concentrations were reported and concentrations returned to normal 7–10 days after the drug was discontinued.¹

Cefditoren pivoxil causes renal excretion of carnitine,¹ and asymptomatic reductions in plasma carnitine concentrations have been reported with short-term (10–14 days) treatment with the drug.¹ The possible effects of repeated short-term use on carnitine concentrations are not known.¹

Cefditoren should not be used in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically important carnitine deficiency.¹ In addition, the fact that some patients (e.g., those with renal impairment or decreased muscle mass) may be at increased risk for reductions in serum carnitine concentrations during cefditoren therapy should be considered.^a

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of cefditoren and other antibacterials, use only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.¹

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.¹ In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.¹

Hematologic Effects

Reduction in prothrombin activity reported rarely with cephalosporins.¹ PT should be monitored and vitamin K administered as indicated in patients at risk for reduced prothrombin activity (e.g., patients with renal or hepatic impairment or poor nutritional status, patients receiving prolonged antimicrobial therapy or previously stabilized on anticoagulant therapy).¹

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; use with caution in nursing women.¹

Pediatric Use

Safety and efficacy (including any effect of altered carnitine concentrations) not established in children <12 years of age;¹ use in this age group not recommended.^{1 3}

Geriatric Use

Safety and efficacy in those >65 years of age similar to that in younger adults.¹

Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function.¹ Select dosage with caution and consider monitoring renal function because of age-related decreases in renal function.¹ (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

AUC increased slightly in adults with mild or moderate hepatic impairment (Child-Pugh class A or B);¹ no dosage adjustments required in these patients.¹

Not studied in patients with severe hepatic impairment (Child-Pugh class C).¹

Renal Impairment

Decreased clearance.¹

Reduce dosage in those with Cl_cr <50 mL/minute.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,^{1 3} nausea,^{1 3} headache,^{1 3} abdominal pain,^{1 3} vaginal moniliasis,^{1 3} dyspepsia,¹ vomiting.^{1 3}

Interactions for Cefditoren Pivoxil

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Antacids (aluminum- or magnesium-containing)	Decreased absorption of cefditoren1	Do not administer antacids containing aluminum or magnesium concomitantly with cefditoren1
Histamine H2-receptor antagonists (famotidine)	Possible decreased absorption of cefditoren	Do not administer H2-receptor antagonists concomitantly with cefditoren1
Hormonal contraceptives	No effect on the pharmacokinetics of ethinyl estradiol	May be used concomitantly with oral contraceptives
Probenecid	Increased cefditoren plasma concentrations and half-life 1
Tests for glucose	Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution1	Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix, Tes-Tape)1

Cefditoren Pivoxil Pharmacokinetics

Absorption

Bioavailability

Cefditoren pivoxil is a prodrug that is absorbed from the GI tract and hydrolyzed by esterases to the active metabolite, cefditoren.¹

Absolute bioavailability only 14% when given without food;¹ peak plasma concentrations of cefditoren attained within 1.5–3 hours.¹

Food

Administration with a moderate- or high-fat meal increases the rate and extent of absorption.¹

Distribution

Extent

Distributed into tonsils and skin blister fluid.¹

Distributed into milk in rats.¹

Plasma Protein Binding

88%;¹ binding is independent of concentration.¹

Binds principally to albumin; 3.3–8.1% bound to α-1-acid glycoprotein.¹

Elimination

Metabolism

Cefditoren pivoxil is a prodrug and has little, if any, antibacterial activity until hydrolyzed in vivo by esterases to cefditoren.¹ Hydrolysis of the drug also results in the formation of pivalate, which is absorbed and excreted as pivaloylcarnitine in urine.¹

Cefditoren is not appreciably metabolized.¹

Elimination Route

Principally eliminated in urine by renal tubular excretion and glomerular filtration.¹

Half-life

Terminal elimination half-life is 1.6 hours in adults with normal renal function.¹

Special Populations

AUC only slightly increased in adults with mild or moderate hepatic impairment (Child-Pugh class A or B).¹ Pharmacokinetics have not been studied in patients with severe hepatic impairment (Child-Pugh class C).¹

Clearance of the drug reduced in those with renal impairment.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹ Protect from light and moisture; dispense in a tight, light-resistant container.¹

Actions and Spectrum

• Third-generation cephalosporin with an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins.^{1 3 4} In addition, the methylthiazolyl group in cefditoren enhances activity against gram-positive bacteria.³

• Cefditoren pivoxil is a prodrug and has little, if any, antibacterial activity until hydrolyzed in vivo to cefditoren.^{1 3}

• Usually bactericidal.¹

• Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.^{1 a}

• In vitro spectrum of activity includes many gram-positive aerobic bacteria and some gram-negative aerobic bacteria; inactive against fungi and viruses.^{1 a}

• Gram-positive aerobes: active in vitro and in clinical infections against Staphylococcus aureus (oxacillin-susceptible strains, including β-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), and Streptococcus pyogenes (group A β-hemolytic streptococci).¹ Also active in vitro against Streptococcus agalactiae (group B streptococci), groups C and G streptococci, and viridans streptococci (penicillin-susceptible and -intermediate strains).¹ Oxacillin-resistant S. aureus (methicillin-resistant S. aureus; MRSA) are resistant.¹

  Gram-negative aerobes: active in vitro and in clinical infections against Haemophilus influenzae (including β-lactamase-producing strains), H. parainfluenzae (including β-lactamase-producing strains), and Moraxella catarrhalis (including β-lactamase-producing strains).¹

Advice to Patients

• Advise patients that antibacterials (including cefditoren) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).¹

• Importance of completing full course of therapy, even if feeling better after a few days.¹

• Advise patients that skipping doses or not completing the full course of therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with cefditoren or other antibacterials in the future.¹

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.^a Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.^a

• Importance of avoiding use of cefditoren tablets in patients with milk protein hypersensitivity (not lactose intolerance).^{1 3}

• Importance of taking cefditoren with meals for optimum absorption.^{1 3}

• Advise patients that cefditoren may be used concomitantly with oral estrogen-progestin contraceptives.^{1 3}

• Importance of discontinuing cefditoren and informing clinician if an allergic reaction occurs.^{1 3}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 3}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 3}

• Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Cefditoren Pivoxil

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	200 mg (of cefditoren)	Spectracef	Cornerstone

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Spectracef 200MG Tablets (CORNERSTONE BIOPHARMA): 20/$299.98 or 40/$575.97

Spectracef 200MG Tablets (CORNERSTONE BIOPHARMA): 60/$342.01 or 180/$992.02