Cefditoren

Cefditoren also known as cefditoren pivoxil (trade names Spectracef, Meiact, and Zostum-O) 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.[1] USFDA (2001) approved Cefditoren pivoxil for adults and adolescents (12 years of age or older).[2] In 2018 Zuventus healthcare ltd received approval for Cefditoren Pivoxil dry powder for suspension (100mg / 5mL) for the treatment of mild to moderate infection also in children’s of (2 months to 12 years of age) which are caused by susceptible strains of the designated microorganisms.[3]

Cefditoren
Clinical data
Trade namesSpectracef, others
AHFS/Drugs.comMonograph
MedlinePlusa605003
Routes of
administration		By mouth
ATC code
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H18N6O5S3
Molar mass506.57 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

Cefditoren pivoxil has an unique action that is Lowering IL6 &K L6 to get rid from lung inflammation and epithelial damage besides bactericidal activity.[4]It was patented in 1984 and approved for medical use in 1994.[5]

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 (Enhances activity against Gram-negative organisms), Methylthiazole group (Enhances activity against gram-positive organisms), Methoxyimino Group (β-lactamase stability), A pivoxil ester group (Enhances oral bioavailability).[6]

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 (PBP 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.[7] Aerobic Gram-Positive Microorganisms: Staphylococcus aureus (methicillin-susceptible strains, including ß-lactamase-producing strains), Streptococcus pneumoniae, Streptococcus pyogenes Aerobic Gram-Negative Microorganisms: Haemophilus influenzae (including ß-lactamase-producing strains), Haemophilus parainfluenzae (including ß-lactamase-producing strains), Moraxella catarrhalis (including ß-lactamase-producing strains.[2]

Pharmacokinetics

Absorption

Oral Bioavailability-following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations (Cmax) 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. Under fasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%.[8]

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.[9]

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. [10]

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 (indications may differ between countries).[11][12]

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 (includes MRSA)
  • Streptococcus pyogenes: ≤0.004 – 2 μg/ml[13]

Cefditoren is a broad-spectrum antibiotic against Gram-negative and Gram-positive bacteria, but does not have antibacterial activity against Pseudomonas aeruginosa.[14]

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- 200mg BID for 10 days
  • Uncomplicated Skin and Skin Structure Infections- 200mg BID for 10 days [15]

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. [16]

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.[15]

Geriatric Use

Of the 2675 patients in clinical studies who received cefditoren pivoxil 200 mg BID, 308 (12%) were >65 years of age. Of the 2159 patients in clinical studies who received cefditoren pivoxil 400 mg BID, 307 (14%) 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 (for their age) 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.[15]

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.[17] Cefditoren is also marketed under the name Meiact by Meiji Seika Pharma Co., Ltd.[18] 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.[15]

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 (e.g. diarrhoea, nausea and abdominal pain) 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 (median daily dose: 10.0 mg/kg with a median total treatment period of 7 days), the incidence of adverse reactions was 1.79%, without unexpected or serious adverse drug reactions reported. The most frequent adverse drug reaction was diarrhea (1.30%) that resolved or subsided during cefditoren treatment or after discontinuation or completion of therapy in all cases.[19]
  • 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 (734 children), the incidence of adverse reactions was 1.50% (11 events in 11 patients), 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 (66 patients) with amoxicillin/clavulanic acid (72 patients) for 10 days in the treatment of acute bacterial rhinosinusitis, the most frequent adverse event was diarrhea, with significant (P = 0.02) differences in the percentages found for both compounds (4.5% with cefditoren vs. 18.1% for amoxicillin/clavulanic acid).[20]

Guidelines

Japanese Guidelines
  1. Japanese Guidelines for the Management of Respiratory Infectious Diseases in Children recommend cefditoren pivoxil as an initial antimicrobial therapy in children (2 months and older).[21]

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 3rd-generation oral cephalosporins, cefditoren pivoxil has the highest intrinsic activity on Streptococcus pneumoniae, penicillin-resistant strains (PEN-R)included.
* 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.[22]

Ideal for Switch over therapy
  • The characteristics of oral antibiotics to be considered for the switch therapy (parenteral to oral antibiotic) are: (i) Similar antimicrobial spectrum (ii) High bioavailability (iii) Administration time 12–24 hr (iv) 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 (like cefotaxime or ceftriaxone) to oral therapy, because of the similar spectrum and the highest intrinsic activity.[22]

References
  1. Wellington K, Curran MP (2004). "Cefditoren pivoxil: a review of its use in the treatment of bacterial infections". Drugs. 64 (22): 2597–618. doi:10.2165/00003495-200464220-00009. PMID 15516158.
  2. USFDA Prescribing information. "Spectracef" (PDF). Retrieved 20 March 2020.
  3. DCGI approval Letter. "Cefditoren" (PDF). Retrieved 20 March 2020.
  4. Blasi F, Tarsia P, Mantero M, Morlacchi LC, Piffer F. Cefditoren versus levofloxacin in patients with exacerbations of chronic bronchitis: serum inflammatory biomarkers, clinical efficacy, and microbiological eradication. Ther Clin Risk Manag. 2013;9:55–64. (2013). "Cefditoren versus levofloxacin in patients with exacerbations of chronic bronchitis: serum inflammatory biomarkers, clinical efficacy, and microbiological eradication". Ther Clin Risk Manag. 9: 55–64. doi:10.2147/TCRM.S41131. PMC 3575210. PMID 23430960.CS1 maint: multiple names: authors list (link)
  5. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 496. ISBN 9783527607495.
  6. Balbisi EA (October 2002). "Cefditoren, a new aminothiazolyl cephalosporin". Pharmacotherapy. 22 (10): 1278–93. doi:10.1592/phco.22.15.1278.33481. PMID 12389878.
  7. Blasi F, Concia E, Del Prato B, Giusti M, Mazzei T, Polistena B, et al. (October 2017). "The most appropriate therapeutic strategy for acute lower respiratory tract infections: a Delphi-based approach". Journal of Chemotherapy. 29 (5): 274–286. doi:10.1080/1120009X.2017.1291467. PMID 28298164.
  8. Wellington K, Curran MP (2004). "Cefditoren pivoxil: a review of its use in the treatment of bacterial infections". Drugs. 64 (22): 2597–618. doi:10.2165/00003495-200464220-00009. PMID 15516158.
  9. Wellington K, Curran MP (2004). "Cefditoren pivoxil: a review of its use in the treatment of bacterial infections". Drugs. 64 (22): 2597–618. doi:10.2165/00003495-200464220-00009. PMID 15516158.
  10. Wellington K, Curran MP (2004). "Cefditoren pivoxil: a review of its use in the treatment of bacterial infections". Drugs. 64 (22): 2597–618. doi:10.2165/00003495-200464220-00009. PMID 15516158.
  11. "Cefditoren Package Insert" (PDF). fda.gov. United States Food and Drug Administration. Retrieved 29 January 2020.
  12. Wellington K, Curran MP (2004). "Cefditoren pivoxil: a review of its use in the treatment of bacterial infections". Drugs. 64 (22): 2597–618. doi:10.2165/00003495-200464220-00009. PMID 15516158.
  13. "Cefditoren sodium Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). TOKU-E. 22 March 2020.
  14. "Disease relevance of Cefditoren". Retrieved June 24, 2014.
  15. USFDA. "Spectracef® (cefditoren pivoxil) Tablets 200 mg and 400 mg" (PDF). Retrieved 27 March 2020.
  16. MEIACT MS FINE GRANULES 10%. "Japanese PI". KEGG DRUG. Retrieved 27 March 2020.
  17. "Cefditoren". fda.gov. United States Food and Drug Administration. Retrieved January 29, 2020.
  18. Meiact Full Description Archived 2010-09-17 at the Wayback Machine
  19. Kawamata S, Yamada H, Sato Y, Sasagawa Y, Iwama Y, Matumoto M (2010). "Evaluation of the Safety and Efficacy of Cefditoren Pivoxil Fine Granules for Pediatric Use in Pediatric Patients With Acute Otitis Media". Jpn J Antibiot. 63 (3): 207–223. PMID 20976878.CS1 maint: multiple names: authors list (link)
  20. Barberán J, Aguilar L, Giménez MJ (2012). "Update on the clinical utility and optimal use of cefditoren". Int J Gen Med. 5: 455–464. doi:10.2147/IJGM.S25989. PMC 3367410. PMID 22675264.CS1 maint: multiple names: authors list (link)
  21. Uehara S, Sunakawa K, Eguchi H (2011). "Japanese Guidelines for the Management of Respiratory Infectious Diseases in Children 2007 with focus on pneumonia". Pediatr Int. 53 (2): 264–276. doi:10.1111/j.1442-200x.2010.03316.x. PMID 21648118.CS1 maint: multiple names: authors list (link)
  22. Blasi F, Concia E, Del Prato B (2017). "The most appropriate therapeutic strategy for acute lower respiratory tract infections: a Delphi-based approach". J Chemother. 29 (5): 274–286. doi:10.1080/1120009X.2017.1291467. PMID 28298164.CS1 maint: multiple names: authors list (link)
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