Cefditoren
Cefditoren also known as cefditoren pivoxil is a third-generation oral cephalosporin with a broad spectrum of activity against pathogens, including both Gram-positive and -negative bacteria, and is stable to hydrolysis by many common beta-lactamases. USFDA approved Cefditoren pivoxil for adults and adolescents. In 2018 Zuventus healthcare ltd received approval for Cefditoren
Pivoxil dry powder for suspension for the treatment of mild to moderate infection also in children’s of which are caused by susceptible strains of the designated microorganisms.
Cefditoren pivoxil has a unique action that is Lowering IL6 &K L6 to get rid from lung inflammation and epithelial damage besides bactericidal activity. It was patented in 1984 and approved for medical use in 1994.
Structure
Like other cephalosporins, Cefditoren has a β-lactam ring at the 7 position of cephalosporin ring, responsible for its cell wall synthesis inhibitory action. In addition to the cephem nucleus common to all cephalosporins cefditoren possesses, Aminothiazole group, Methylthiazole group, Methoxyimino Group, A pivoxil ester group .Antimicrobial activity
The spectrum of cefditoren is particularly balanced, including both Gram-positive and Gram-negative species. Strong antimicrobial activity because of the high affinity of the cefditoren for the Penicillin Binding Protein 2X, responsible for cephalosporin resistance when mutated. Cefditoren pivoxil has the highest intrinsic activity on S. pneumoniae, penicillin-resistant strains included. Cefditoren holds a balanced antimicrobial spectrum that includes the three major pathogens of community- acquired LRTIs: S. pneumoniae, H. influenzae and M. Catarrhalis.Aerobic Gram-Positive Microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes
Aerobic Gram-Negative Microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis (including ß-lactamase-producing strains.
Pharmacokinetics
Absorption
Oral Bioavailability-following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations of cefditoren under fasting conditions average 1.8 ± 0.6 µg/mL following 200 mg dose and occur 1.5 to 3 hours following dosing. Cefditoren does not accumulate in plasma following twice daily administration to subjects with normal renal function. Underfasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%.
Distribution
Binding of cefditoren to plasma proteins averages 88%, and the mean volume of distribution of cefditoren at steady state is 9.3L.Cefditoren has been shown to penetrate into bronchial mucosa, epithelial lining fluid, skin blister fluid and tonsillar tissue and clinically relevant concentrations against common pathogens are achieved in these tissues for at least 4 hours.
Metabolism and Excretion
Cefditoren is predominantly eliminated by the kidneys as unchanged drug and has a renal clearance of 4.1–5.6 L/h after multiple doses; its elimination half-life is 1.5 hours.Medical uses
Cefditoren pivoxil is indicated to treat uncomplicated skin and skin structure infections, community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, pharyngitis, and tonsillitis,acute maxillary sinusitis, otitis media.Spectrum of bacterial susceptibility
Cefditoren pivoxil has a broad spectrum of activity and has been used to treat bacterial infections of the skin and respiratory tract, including bronchitis, pneumonia, and tonsillitis. The following represents minimum inhibitory concentration data for several medically significant microorganisms.- Haemophilus influenzae: ≥0.063 – 0.25 μg/ml
- Staphylcoccus aureus: 0.25 – >128 μg/ml
- Streptococcus pyogenes: ≤0.004 – 2 μg/ml
Dosage and Administration
Adults and Adolescents (≥12 Years)
- Community-Acquired Pneumonia- 400 mg BID for 14 days
- Acute Bacterial Exacerbation of Chronic Bronchitis -400 mg BID for 10 days
- Pharyngitis/Tonsillitis, otitis media, sinusitis- 200 mg BID for 10 days
- Uncomplicated Skin and Skin Structure Infections- 200 mg BID for 10 days
Children (2 months to 12 years of age)
- Pneumonia, otitis media or sinusitis: 3 mg/kg/dose, 3 times a day, after meals. The dosage may be increased up to 6 mg/kg/dose as needed, but not exceed the maximum dose for adults.
- For children with diseases other than above: 3 mg/kg/dose, 3 times a day after meals. The dosage may be adjusted according to the disease or the patients age and symptoms, but not exceed the maximum dose for adults. Safety in low birth weight infants and newborns has not been established.
Pregnancy
Pregnancy Category B
Cefditoren pivoxil was not teratogenic up to the highest doses tested in rats and rabbits. In rats, this dose was 1000 mg/kg/day, which is approximately 24 times a human dose of 200 mg BID based on mg/m2/day. In rabbits, the highest dose tested was 90 mg/kg/day, which is approximately four times a human dose of 200 mg BID based on mg/m2/day. This dose produced severe maternal toxicity and resulted in fetal toxicity and abortions.In a postnatal development study in rats, cefditoren pivoxil produced no adverse effects on postnatal survival, physical and behavioral development, learning abilities, and reproductive capability at sexual maturity when tested at doses of up to 750 mg/kg/day, the highest dose tested. This is approximately 18 times a human dose of 200 mg BID based on mg/m2/day. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Geriatric Use
Of the 2675 patients in clinical studies who received cefditoren pivoxil 200 mg BID, 308 were >65 years of age. Of the 2159 patients in clinical studies who received cefditoren pivoxil 400 mg BID, 307 were >65 years of age. No clinically significant differences in effectiveness or safety were observed between older and younger patients. No dose adjustments are necessary in geriatric patients with normal renal function. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.International Approvals
Cefditoren pivoxil is available as 200 and 400 mg tablets in the United States. It was marketed under the trade name Spectracef by Vansen Pharma Inc. Cefditoren is also marketed under the name Meiact by Meiji Seika Pharma Co., Ltd. In INDIA it is currently marketed under the brand name "Zostum-O" by Zuventus healthcare ltd.Proprietary Preparations and Countries
US:Spectracef; India:Zostum-O; Japan:Meiact; Russia:Spectracef; China:Meiact; Greece:Spectracef; Indonesia:Meiact; Italy:Giasion; Mexico:Spectracef; Portugal:Meiact; Thialand:Meiact; Turkey: Cftiten, Meiact; Sefporin Spain: Spectracef, Meiact.Contraindications
- In patients with known allergy to the cephalosporin class of antibiotics or any of its components.
- Patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency, because use of cefditoren causes renal excretion of carnitine.
Safety and Tolerability
- Cefditoren pivoxil is generally well tolerated, with most adverse events being of mild-to-moderate severity and self-limiting. Gastrointestinal adverse events were the most commonly reported adverse events, although they seldom led to treatment discontinuation.
- In a postmarketing surveillance evaluating safety in 2006 children with acute otitis media treated with cefditoren, the incidence of adverse reactions was 1.79%, without unexpected or serious adverse drug reactions reported. The most frequent adverse drug reaction was diarrhea that resolved or subsided during cefditoren treatment or after discontinuation or completion of therapy in all cases.
- Data from the clinical studies carried out with cefditoren in the treatment of pharyngotonsillitis from 2007 to 2010 in Japan showed that the percentage of adverse events was very low and diarrhea was the most frequent event. In the largest study, the incidence of adverse reactions was 1.50%, with 3 events of diarrhea and three of hematuria in urinalysis without clinical symptoms. In a study carried out in children in Thailand comparing cefditoren with amoxicillin/clavulanic acid for 10 days in the treatment of acute bacterial rhinosinusitis, the most frequent adverse event was diarrhea, with significant differences in the percentages found for both compounds.
Guidelines
Japanese Guidelines
- Japanese Guidelines for the Management of Respiratory Infectious Diseases in Children recommend cefditoren pivoxil as an initial antimicrobial therapy in children.
A panel of 70 pulmonologists, coordinated by 9 experts in respiratory care recommendations
- A consensus on appropriate prescribing in LRTI therapy was appraised by Delphi exercise, based on a panel of 70 pulmonologists, coordinated by a Scientific Committee of nine experts in respiratory medical care.
* Amongst III-generation oral cephalosporins, the spectrum of cefditoren is particularly balanced, includes both Gram-positive and Gram-negative species.
* The experts expressed the opinion that, due to its high intrinsic activity, cefditoren appears as an appropriate agent for either the treatment of LRTIs and for parenteral to oral switch therapy as well.
Ideal for Switch over therapy
- The characteristics of oral antibiotics to be considered for the switch therapy are: Similar antimicrobial spectrum High bioavailability Administration time 12–24 hr Good tolerability
- The expert panel reached a high level of consensus on cefditoren pivoxil as the most appropriate option for the switch therapy from parenteral third-generation cephalosporins to oral therapy, because of the similar spectrum and the highest intrinsic activity.