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Cefditoren Pivoxil

Cefditoren pivoxil is a semisynthetic cephalosporin antibiotic. The drug is an oral aminothiazolyl cephalosporin with a methylthiazolyl group at position 3 of the cephalosporin nucleus. Cefditoren pivoxil is a prodrug and has little, if any, antibacterial activity until hydrolyzed in vivo to cefditoren.

Following oral administration of cefditoren pivoxil, the drug is absorbed from the GI tract and hydrolyzed by esterases to cefditoren. Hydrolysis of cefditoren pivoxil also results in the formation of pivalate, which is absorbed and excreted as pivaloylcarnitine in urine.

Cefditoren is not appreciably metabolized. The drug is eliminated principally unchanged by renal excretion. Based on its spectrum of activity, cefditoren is classified as a third generation cephalosporin.

Cefditoren Pivoxil

Cefditoren is stable in the presence of a variety of b-lactamases (including penicillinases and some cephalosporinases) produced by gram-positive and -negative bacteria.

Like other currently available third generation cephalosporins (e.g., cefdinir, cefixime, ceftibuten, cefpodoxime), cefditoren has an expanded spectrum of activity against gram-negative bacteria compared with first and second generation cephalosporins; however, the methylthiazolyl group in cefditoren, which also is found in first generation cephalosporins but not in other currently available third generation cephalosporins, enhances activity of cefditoren against gram-positive bacteria.

Cefditoren is active in vitro and in clinical infections against most strains of Staphylococcus aureus (methicillin-susceptible strains, including b-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), Streptococcus pyogenes (group A b-hemolytic streptococci), Haemophilus influenzae (including b-lactamase-producing strains), H. parainfluenzae (including b-lactamase-producing strains), and Moraxella (formerly Branhamella) catarrhalis (including b-lactamase-producing strains). Cefditoren also has demonstrated in vitro activity against S. agalactiae (group B streptococci), groups C and G streptococci, and viridans streptococci (penicillin-susceptible and -intermediate strains); however, the safety and efficacy of cefditoren in treating clinical infections caused by these microorganisms have not been established in adequate and well-controlled clinical trials to date.

Uses

Respiratory Tract Infections

Cefditoren pivoxil is used for the treatment of mild to moderate acute bacterial exacerbations of chronic bronchitis caused by susceptible strains of Haemophilus influenzae (including b-lactamase-producing strains), H. parainfluenzae (including b-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including b-lactamase-producing strains).

Pharyngitis and Tonsillitis

Cefditoren pivoxil is used for the treatment of pharyngitis and tonsillitis caused by susceptible strains of Streptococcus pyogenes. Although cefditoren usually is effective in eradicating S. pyogenes from the nasopharynx, efficacy of the drug in the subsequent prevention of rheumatic fever remains to be established. Because penicillin has a narrow spectrum of activity, is inexpensive, and generally effective, the US Centers for Disease Control and Prevention (CDC), American Academy of Pediatrics (AAP), American Academy of Family Physicians (AAFP), Infectious Diseases Society of America (IDSA), American Heart Association (AHA),American College of Physicians-American Society of Internal Medicine (ACP-ASIM), and others consider natural penicillins (i.e., 10 days of oral penicillin V or a single IM dose of penicillin G benzathine) the treatment of choice for streptococcal pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever, although oral amoxicillin often is used instead of penicillin V in small children because of a more acceptable taste. Other anti-infectives (e.g., oral cephalosporins, oral macrolides) generally are considered alternatives.

Skin and Skin Structure Infections

Cefditoren pivoxil is used orally for the treatment of uncomplicated skin and skin structure infections caused by susceptible strains of Staphylococcus aureus (including b-lactamase-producing strains) or S. pyogenes. For additional information on these and other uses of cephalosporins, see Uses in the Cephalosporins General Statement 8:12.06

Dosage and Administration

General

Cefditoren pivoxil is administered orally with meals (to enhance GI absorption). Dosage of cefditoren pivoxil is expressed in terms of cefditoren. The usual dosage of cefditoren for the treatment of acute bacterial exacerbations of chronic bronchitis in adults and adolescents 12 years of age or older is 400 mg twice daily for 10 days. For the treatment of pharyngitis and tonsillitis or uncomplicated skin and skin structure infections in adults and adolescents 12 years of age or older, the usual dosage is 200 mg twice daily for 10 days.

Special Populations

No dosage adjustment is necessary in patients with mild renal impairment (creatinine clearance of 50-80 mL/min per 1.73 m); however, the manufacturer recommends a maximum dosage of 200 mg twice daily for patients with moderate renal impairment (creatinine clearance of 30-49 mL/min per 1.73 m) and a dosage of 200 mg once daily for those with severe renal impairment (creatinine clearance <30 mL/min per 1.73 m).

The appropriate dosage in patients with end-stage renal disease has not been determined. The manufacturer states that no dosage adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The pharmacokinetics of cefditoren have not been studied in patients with severe hepatic impairment (Child-Pugh class C). No special dosage recommendations at this time for geriatric patients with normal renal function.

Cautions

Contraindications

Known hypersensitivity to cefditoren, other cephalosporins, or any ingredient in the formulation. Carnitine deficiency or an inborn error of metabolism that may result in clinically important carnitine deficiency. Milk protein hypersensitivity (not lactose intolerance).

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

There is clinical and laboratory evidence of partial cross-sensitivity among cephalosporins and other b-lactam antibiotics. Cefditoren pivoxil should be used with caution in patients with a history of hypersensitivity to penicillins; the drug should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins.

Cefditoren should be discontinued if a hypersensitivity reaction occurs and the patient treated with appropriate therapy (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen) as indicated.

Major Toxicities

Clostridium difficile-associated Colitis Reported with numerous anti-infectives, including cefditoren pivoxil; may range in severity from mild to life-threatening. Evaluate and monitor patients who develop diarrhea during therapy.

General Precautions

Carnitine Deficiency

Prolonged use of other pivalate-containing compounds has been associated with clinical manifestations of carnitine deficiency.

The manufacturer recommends that cefditoren pivoxil not be used when prolonged anti-infective therapy is required. Asymptomatic reductions in plasma carnitine concentrations have been associated with short-term (10-14 days) treatment with cefditoren pivoxil.

The effects on carnitine concentrations with repeated short-term use are not known at this time.

Bacterial or Fungal Overgrowth

Following prolonged or repeated therapy, overgrowth of nonsusceptible bacteria or fungi may occur.

Appropriate therapy should be instituted if such infections occur.

Hematologic Effects

Reduction in prothrombin activity reported rarely with cephalosporins. The manufacturer recommends that prothrombin time (PT) 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). Specific Populations Pregnancy Category B. (See Users Guide.)

Lactation

Cefditoren is distributed into milk in rats; caution if used in nursing women.

Pediatric Use

Safety and efficacy not established in children younger than 12 years of age. Geriatric Use No substantial differences in safety and efficacy relative to younger adults.

Common Adverse Effects

Adverse effects occurring in 1% or more of patients receiving cefditoren include diarrhea, nausea, headache, abdominal pain, vaginal moniliasis, dyspepsia, and vomiting.

Drug Interactions

Antacids and H2-Receptor Antagonists

Pharmacokinetic interaction (decreased absorption of cefditoren). The manufacturer recommends that cefditoren not be administered concomitantly with antacids or H2-receptor antagonists; however, the clinical importance of this interaction has not been established.

Probenecid

Pharmacokinetic interaction (increased plasma concentrations of cefditoren).

Oral Contraceptives

No effect on the pharmacokinetics of ethinyl estradiol observed.

Advice to Patients

Necessity for patients with milk protein hypersensitivity (not lactose intolerance) to avoid taking cefditoren pivoxil tablets. Importance of taking cefditoren pivoxil tablets with meals for optimum absorption.

Cefditoren may be used concomitantly with oral estrogen-progestin contraceptives. Importance of monitoring for signs of hypersensitivity. Importance of reporting persistent or worsening symptoms of infection. Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and nonprescription drugs.

Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Cefditoren Pivoxil Oral Tablets, film- 200 mg (of cefditoren) Spectracef®, (with sodium coated caseinate) TAP Pharmaceuticals

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