Cefditoren

Cefditoren
Names
Trade namesSpectracef, Meiact, Zostum-O, others
Other namesCephditoren, cefditoren pivoxil
IUPAC name
  • (7R)-7-((Z)-2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Clinical data
Drug classAntibiotic (3rd generation cephalosporin)[1]
Main usesStrep throat, respiratory tract infections, skin and skin structure infections[2]
Side effectsNausea, diarrhea, headache, heart burn, vaginal yeast infection[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
External links
AHFS/Drugs.comMonograph
MedlinePlusa605003
Chemical and physical data
FormulaC19H18N6O5S3
Molar mass506.57 g·mol−1
3D model (JSmol)
SMILES
  • O=C3N2/C(=C(/C=C\c1scnc1C)CS[C@@H]2[C@@H]3NC(=O)C(=N\OC)/c4nc(sc4)N)C(=O)O
InChI
  • InChI=1S/C19H18N6O5S3/c1-8-11(33-7-21-8)4-3-9-5-31-17-13(16(27)25(17)14(9)18(28)29)23-15(26)12(24-30-2)10-6-32-19(20)22-10/h3-4,6-7,13,17H,5H2,1-2H3,(H2,20,22)(H,23,26)(H,28,29)/b4-3-,24-12-/t13-,17-/m1/s1 checkY
  • Key:KMIPKYQIOVAHOP-YLGJWRNMSA-N checkY

Cefditoren, sold under the brand name Spectracef among others, is an antibiotic used to treat strep throat, respiratory tract infections, and skin and skin structure infections.[2] It is effective against both Gram-positive and Gram-negative bacteria.[3] It is taken by mouth with food.[2]

Common side effects include nausea, diarrhea, headache, heart burn, and vaginal yeast infection.[2] Other side effects may include Clostridioides difficile infection and allergic reactions.[2] There is no evidence of harm in pregnancy but such use has not been well studied.[4] It is a third-generation cephalosporin and works by interfering with the bacterial cell wall.[1]

Cefditoren was patented in 1984 and approved for medical use in 1994.[5] It was approved for medical use in the United States in 2001.[2] It is no longer commercially available in the United States as of 2021.[6]

Medical uses

Cefditoren is used to treat uncomplicated skin and skin structure infections, community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, pharyngitis, and tonsillitis, acute maxillary sinusitis, and otitis media.[7][3]

Antimicrobial activity

The spectrum of cefditoren includes both Gram-positive and Gram-negative bacterial species. It has strong antimicrobial activity because of its high affinity for penicillin binding protein 2X, which responsible for cephalosporin resistance when mutated. Cefditoren pivoxil high intrinsic activity against Streptococcus pneumoniae, including penicillin-resistant strains. Cefditoren holds a balanced antimicrobial spectrum that includes the three major pathogens of community-acquired lower-respiratory tract infections: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.[8] Aerobic Gram-positive microorganisms: Staphylococcus aureus (methicillin-susceptible strains, including β-lactamase-producing strains), Streptococcus pneumoniae, Streptococcus pyogenes Aerobic Gram-negative microorganisms: Haemophilus influenzae (including β-lactamase-producing strains), Haemophilus parainfluenzae (including ß-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains.[9]

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.

Cefditoren does not have antibacterial activity against Pseudomonas aeruginosa.[12]

Older people

No differences in effectiveness or safety were observed between older and younger people. No dose adjustments are necessary in geriatric patients with normal renal function. This drug is 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.[13]

Switch 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 hours, (iv) good tolerability
  • The expert panel reached a high level of consensus on cefditoren 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.[14]

Dosage

Adults

  • Community-acquired pneumonia: 400 mg twice daily for 14 days
  • Acute bacterial exacerbation of chronic bronchitis: 400 mg twice daily for 10 days
  • Pharyngitis/tonsillitis, otitis media, sinusitis: 200 mg twice daily for 10 days
  • Uncomplicated skin and skin structure infections: 200 mg twice daily for 10 days[13]

Children

  • 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.[15]

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.[13]

Side effects

Maculopapular rash after receiving cefditoren
  • 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 post-marketing 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 treatment or after discontinuation or completion of therapy in all cases.[16]
  • 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).[17]

Pregnancy

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 twice daily 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 twice daily 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 twice daily 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.[13]

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. Under fasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%.[3]

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.[3]

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.[3]

Structure

Like other cephalosporins, cefditoren has a β-lactam ring at the 7 position of cephalosporin ring that is responsible for its inhibitory action on bacterial cell wall synthesis. In addition to the cephem nucleus common to all cephalosporins, cefditoren has an aminothiazole group that enhances its activity against Gram-negative organisms, a methylthiazole group that enhances its activity against Gram-positive organisms, a methoxyimino group that gives it stability against β-lactamases, and a pivoxil ester group that enhances oral bioavailability.[18]

Society and culture

Brands

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.[19] Cefditoren is also marketed under the name Meiact by Meiji Seika Pharma Co., Ltd.[20] In India it is marketed under the brand name Zostum-O by Zuventus Healthcare.

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.

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]

The experts expressed the opinion that, due to its high intrinsic activity, cefditoren appears as an appropriate agent for either the treatment of lower respiratory tract infections and for parenteral to oral switch therapy as well.[14]

References

  1. 1 2 Beauduy, Camille E.; Winston, Lisa G. (2020). "43. Beta-lactam and other cell wall - & membrane - active antibiotics". In Katzung, Bertram G.; Trevor, Anthony J. (eds.). Basic and Clinical Pharmacology (15th ed.). New York: McGraw-Hill. p. 832. ISBN 978-1-260-45231-0. Archived from the original on 2021-10-10. Retrieved 2021-11-30.
  2. 1 2 3 4 5 6 7 "Cefditoren Monograph for Professionals". Drugs.com. Archived from the original on 26 January 2021. Retrieved 30 December 2021.
  3. 1 2 3 4 5 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. S2CID 46961914.
  4. ↑ "Cefditoren (Spectracef) Use During Pregnancy". Drugs.com. Archived from the original on 28 November 2020. Retrieved 30 December 2021.
  5. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 496. ISBN 9783527607495. Archived from the original on 2021-06-19. Retrieved 2021-07-20.
  6. ↑ "Drugs@FDA: FDA-Approved Drugs". www.accessdata.fda.gov. Archived from the original on 27 August 2021. Retrieved 30 December 2021.
  7. ↑ "Cefditoren Package Insert" (PDF). fda.gov. United States Food and Drug Administration. Archived (PDF) from the original on 9 April 2021. Retrieved 29 January 2020.
  8. ↑ 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.
  9. ↑ USFDA Prescribing information. "Spectracef" (PDF). Archived (PDF) from the original on 9 April 2021. Retrieved 20 March 2020.
  10. ↑ "21-222_Spectracef_microbr" (PDF). Tap holdings inc. 26 June 2001. Archived (PDF) from the original on 20 July 2021. Retrieved 20 July 2021.
  11. ↑ "Cefditoren sodium Susceptibility and Minimum Inhibitory Concentration (MIC) Data" (PDF). TOKU-E. 22 March 2020. Archived (PDF) from the original on 4 March 2016. Retrieved 20 July 2021.
  12. ↑ "Disease relevance of Cefditoren". Archived from the original on July 26, 2014. Retrieved June 24, 2014.
  13. 1 2 3 4 USFDA. "Spectracef® (cefditoren pivoxil) Tablets 200 mg and 400 mg" (PDF). Archived (PDF) from the original on 11 April 2021. Retrieved 27 March 2020.
  14. 1 2 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ↑ "Japanese PI". Kegg Drug. Archived from the original on 13 September 2021. Retrieved 27 March 2020.
  16. ↑ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ↑ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ↑ Balbisi EA (October 2002). "Cefditoren, a new aminothiazolyl cephalosporin". Pharmacotherapy. 22 (10): 1278–93. doi:10.1592/phco.22.15.1278.33481. PMID 12389878.
  19. ↑ "Cefditoren". fda.gov. United States Food and Drug Administration. Archived from the original on August 27, 2021. Retrieved January 29, 2020.
  20. ↑ Meiact Full Description Archived 2010-09-17 at the Wayback Machine
  21. ↑ Uehara S, Sunakawa K, Eguchi H (2011). "Japanese Guidelines for the Management of Respiratory Infectious Diseases in Children 2007 with focus on pneumonia". Pediatrics International. 53 (2): 264–276. doi:10.1111/j.1442-200x.2010.03316.x. PMID 21648118.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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