Cefditoren Pivoxil: Clinical, Pharmacological, and Microbiological Aspects

Clinical Microbiology and Antimicrobial Chemotherapy. 2014; 16(2):111-129

​ Kozlov R.S., Dekhnich A.V.
cefditoren oral cephalosporins sinusitis pharyngitis pneumonia exacerbation of chronic bronchitis skin and soft tissue infections
Section
Antimicrobials
Type
Journal article
Publication
Clinical Microbiology and Antimicrobial Chemotherapy. 2014; 16(2):111-129

Abstract

Cefditoren is a 3rd generation, broad-spectrum oral cephalosporin recently approved for the treatment of acute sinusitis, streptococcal pharyngitis/tonsillitis, bacterial exacerbation of chronic bronchitis, community-acquired pneumonia, and uncomplicated skin/skin structure infections in adult patients and children older than 12 years. This article reviews the antimicrobial activity, pharmacokinetics, evidence based data on the efficacy and safety of cefditoren by the MEDLINE search (up to the June 2013). In the article we also present the data on in vitro activity of cefditoren against recently collected in different regions of Russia community-acquired respiratory pathogens. Cefditoren has a broad spectrum of activity against major community-acquired aerobic bacterial pathogens, including Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Staphylococcus aureus, and enterobacteria. This antimicrobial provides the best coverage for community-acquired respiratory pathogens and for bacteria causing community-acquired skin and soft tissue infections among all oral cephalosporins. Cefditoren is proven to be effective in the management of upper (sinusitis and pharyngitis/tonsillitis) and lower (community-acquired pneumonia and exacerbation of chronic bronchitis) respiratory tract infections, as well as uncomplicated skin/skin structure infections. According to the data reviewed we can conclude that based on its reported antimicrobial activity and data on its clinical efficacy and safety cefditoren has an excellent potential for empiric management of most commonly encountered bacterial community-acquired respiratory tract infections, and, with lesser extent, uncomplicated skin and soft tissue infections.

  • 1. Sakagami K., Atsumi K., Yamamoto Y., et al. Synthesis and oral activity of pivaloyloxymethyl7-I(Z)-2-(2- aminothiazol-4-yl)-2-methoxyiminoacetamido]-3(Z)-(4- methyl-ol-5-yl)vinyl-3-cephem-carboxylate (ME1207) and its related compound. Chem Pharm Bull 1991; 39:2433-6.
  • 2. Spectracef [package insert]. Lake Forest, Ill: TAP Pharmaceuticals; 2001.
  • 3. Kuti J.L., Quintiliani R. Cefditoren pivoxil: a novel broadspectrum oral cephalosporin. Formulary 2001; 36:265-75.
  • 4. Yamada M., Watanabe T., Miyara T., et al. Crystal structure of cefditoren complexed with Streptococcus pneumoniae penicillin-binding protein 2X: structural basis for its high antimicrobial activity. Antimicrob Agents Chemother 2007; 51:45-50.
  • 5. Guay D.R. Review of cefditoren, an advanced-generation, broad-spectrum oral cephalosporin. Clin Ther 2001; 23:1924-37.
  • 6. Li J.T., Hou F., Lu H., Li T.Y., Li H. Phase 1 clinical trial of cefditoren pivoxil (ME 1207): pharmacokinetics in healthy volunteers. Drugs Exp Clin Res 1997; 23:145-50.
  • 7. Guay D. Review of cefditoren, an advanced-generation, broad-spectrum oral cephaospon. Clinical thrapeutics 2001; 23:1924-37.
  • 8. TAP Pharmaceuticals Inc. Spectracef (cefditoren) package insert. Lake Forest, IL; 2001.
  • 9. Tedec-Meiji Farma S.A. Summary of product characteristics: Spectracef® film-coated tablets. Madrid: TedecMeiji Farma S.A., 2004.
  • 10. Sawchuk R.J., Mulford D.J., Mayer M.D. Pharmacokinetics of a new cephalosporin. J Respir Dis 2001; 22(suppl 8):43-51.
  • 11. Purdue Pharmaceutical Products L.P. Package insert: Spectracef tablets (cefditoren pivoxil). Available from URL: http://www.pharma.com/PI/Prescription/spectracef.pdf
  • 12. Mayer M., Mulford D., Witt G. Pharmacokinetics of cefditoren in blister fluid and plasma [abstract no. 656]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17-20; Toronto.
  • 13. Mulford D., Mayer M., Witt G. Effect of age and gender on the pharmacokinetics of cefditoren [poster no. 310]. 40th Inter science Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17-20; Toronto.
  • 14. Mulford D., Mayer M., Witt G. Effect of renal impairment on the pharmacokinetics of cefditoren [poster no. 311]. 40th Inter science Conference on Antimicrobial Agents and Chemother apy; 2000 Sep 17-20; Toronto.
  • 15. Mayer M., Mulford D., Witt G. Effect of hepatic impairment on the pharmacokinetics of cefditoren [poster no. 312]. 40th Inter science Conference on Antimicrobial Agents and Chemother apy; 2000 Sep 17-20; Toronto.
  • 16. Mayer M., Mulford D., Witt G. Effect of an H2 receptor ant agonist or an antacid on the pharmacokinetics of cefditoren [poster no. 313]. 40th Interscience Conference on Anti microbial Agents and Chemotherapy; 2000 Sep 17-20; Toronto.
  • 17. Kinzig-Schippers M., Hinder M., Geohler K., et al. Tissue penetration of cefditoren (CEE) into bronchial mucosa (BM) and epithelial lining fluid (ELF) in patients undergoing fiberoptic bronchoscopy [abstract no. 946]. 41st Interscience Conference on Antimicrobials Agents and Chemotherapy; 2001 Dec 16-19; Chicago.
  • 18. Felmingham D., Robbins M.J., Ghosh G., et al. An in vitro characterization of cefditoren, a new oral cephalosporin. Drugs Exp Clin Res 1994; 20:127-47.
  • 19. Sevillano D., Aguilar L., Alou L., et al. Urine bactericidal activity against Escherichia coli isolates exhibiting different resistance phenotypes/genotypes in an in vitro pharmacodynamic model simulating urine concentrations obtained after oral administration of a 400-milligram single dose of cefditoren-pivoxil. Antimicrob Agents Chemother 2008; 52:1184-86.
  • 20. Brass E.P. Pivalate-generating prodrugs and carnitin homeostasis in man. Pharmacol Rev 2002; 54:589-98.
  • 21. Brass E.P., Mayer M.D., Mulford D.J., Stickler T.K., Hoopel C.L. Impact on carnitine homeostasis of shortterm treatment with the pivalate prodrug cefditoren pivoxil. Clin Pharmacol ther 2003; 73:338-47.
  • 22. Mulford D., Mayer M., Witt G. Effect of cefditoren on the pharmacokinetics of ethinyl estradiol [abstract no. 314]. 40th Interscience Conference on Antimicrobials Agents and Chemotherapy; 2000 Sep 17-20; Toronto.
  • 23. Tomasz A., Holtje J.V. Murein hydrolases and the lytic and killing action of penicillin. In: Microbiology. Schlessinger D. ed. American Society for Microbiology, Washington, D.C., 1977, pp. 209-15.
  • 24. Holtje J.V., Tomasz A. Lipoteichoic acid: a specific inhibitor of autolysin activity in pneumococcus. Proc Nat Acad Sci USA 1975; 72:1690-4.
  • 25. Tomasz A. The mechanism of the irreversible antimicrobial effects of penicillins: how the β-lactam antibiotics kill and lyse bacteria. Annu Rev Microbiol 1979; 33:113-37.
  • 26. Nagai K., Davies T., Jacobs M., et al. Affinity of penicillin-binding proteins (PBP) 1A, 2X and 2B for amoxicillin (AX), cefditoren (CD) and other β-lactams among 18 Streptococcal pneumoniae (Sp) clinical isolates [abstract no. 647a]. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; 2001 Dec 16-19; Chicago.
  • 27. Watanabe Y., Hatano K., Matsumoto Y., et al. In vitro antibacterial activity of FK041, a new orally active cephalosporin. J Antibiot (Tokyo) 1999; 52:649-59.
  • 28. Shimizu M., Takata T.,vMasuyoshi S., et al. Antibacterial activity, bactericidal effect and β-lactamase stability of CDTR, and its binding affinity to PBPs against clinical isolate of Haemophilus influenzae. Jpn J Chemother 1995; 43:815-20.
  • 29. Wellington K., Curran M.P. Cefditoren pivoxil. A review of its use in the treatment of bacterial infections. Drugs 2004; 64:2597-618.
  • 30. Tempera G., Furneri P.M., Carlone N.A., et al. Antibiotic susceptibility of respiratory pathogens recently isolated in Italy: focus on cefditoren. J Chemother 2010; 22:153-9.
  • 31. Biedenbach D.J., Jones R.N. Update of cefditoren activity tested against community-acquired pathogens associated with infections of the respiratory tract and skin and skin structures, including recent pharmacodynamic considerations. Diagn Microbiol Infect Dis 2009; 64:202-12.
  • 32. Fenoll A., Gimenez M.J., Robledo O., et al. Influence of penicillin/amoxicillin non-susceptibility on the activity of third-generation cephalosporins against Streptococcus pneumoniae. Eur J Clin Microbiol Infect Dis 2008; 27:75-80.
  • 33. Fritsche T.R., Biedenbach D.J., Jones R.N. Update of the activity of cefditoren and comparator oral beta-lactam agents tested against community-acquired Streptococcus pneumoniae isolates (USA, 2004-2006). J Chemother 2008; 20:170-4.
  • 34. Seral C., Suarez L., Rubio-Calvo C., et al. In vitro activity of cefditoren and other antimicrobial agents against 288 Streptococcus pneumoniae and 220 Haemophilus influenza clinical strains isolated in Zaragoza, Spain. Diagn Microbiol Infect Dis 2008; 62:210-5.
  • 35. Stefani S., Mezzatesta M.L., Fadda G., et al. Antibacterial activity of cefditoren against major community-acquired respiratory pathogens recently isolated in Italy. J Chemother 2008; 20:561-9.
  • 36. Козлов Р.С. Перспективы применения новых цефалоспоринов в терапии пневмококковых инфекций. Пульмонология 2011; (3):53-8.
  • 37. Biedenbach D.J., Jones R.N., Fritsche T.R. Antimicrobial activity of cefditoren tested against contemporary (2004- 2006) isolates of Haemophilus influenzae and Moraxella catarrhalis responsible for community-acquired respiratory tract infections in the United States. Diagn Microbiol Infect Dis 2008; 61:240-4.
  • 38. Garcia-De-Lomas J., Lerma M., Cebrian L., et al. Influence of Haemophilus influenzae beta-lactamase production and/or ftst gene mutations on in vitro activity of and susceptibility rates to aminopenicillins and secondand third-generation cephalosporins. Int J Antimicrob Agents 2007; 30:190-2.
  • 39. Report on multicenter study of susceptibility to cefditoren of clinical strains of Streptococcus pneumoniae, Haemophilus influenzae, and Streptococcus pyogenes in Russia. Institute of Antimicrobial Chemotherapy, Smolensk, 2010 (data on file).
  • 40. Hatzaki D., Poulakou G., Katsarolis I., et al. Cefditoren: comparative efficacy with other antimicrobials and risk factors for resistance in clinical isolates causing UTIs in outpatients. BMC Infectious Diseases 2012, 12:228-37.
  • 41. Jones R.N., Pfaller M.A., Jacobs M.R., et al. Cefditoren in vitro activity and spectrum: a review of international studies using reference methods. Diagn Microbiol Infect Dis 2001; 41:1-14.
  • 42. Spangler S.K., Jacobs M.R., Appelbaum P.C. Time-kill studies on susceptibility of nine penicillin-susceptible and -resistant pneumococci to cefditoren compared with nine other β-lactams. J Antimicrob Chemother 1997; 39:141-8.
  • 43. Soriano F., Coronel P., Gimeno M., et al. Inoculum effect and bactericidal activity of cefditoren and other antibiotics against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Eur J Clin Microbiol Infect Dis 1996; 15:761-3.
  • 44. Craig W.A. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:1-10.
  • 45. Heffelfinger J.D., Dowell S.F., Jorgensen J.H., et al. Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group. Arch Intern Med 2000; 160:1399-408.
  • 46. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; nineteenth informational supplement. CLSI document M100-S19. Clinical and Laboratory Standards Institute, Wayne, PA, USA; 2009.
  • 47. Granizo J.J, Sбdaba B., Honorato J., et al. Monte Carlo simulation describing the pharmacodynamic profile of cefditoren in plasma from healthy volunteers. Int J Antimicrob Agents 2008; 31:396-8.
  • 48. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; nineteenth informational supplement. CLSI document M100-S23. Clinical and Laboratory Standards Institute, Wayne, PA, USA; 2013.
  • 49. Clark C.L., Nagai K., Dewasse B.E., Pankuch G.A., Ednie L.M., Jacobs M.R., Appelbaum P.C. Activity of cefditoren against respiratory pathogens. J Antimicrob Chemother 2002; 50:33-41.
  • 50. Blasi F., Concia E., Mazzei T., Moretti AM.., Nicoletti G., Novelli A., Tempera G. Role of the oral beta-lactams in the treatment of exacerbations of chronic bronchitis: critical analysis and therapeutics recommendations. J Chemother 2010; 22 (Suppl 1):3-4.
  • 51. Di Marco F., Braido F., Santus P., Scichilone N., Blasi F. The role of cefditoren in the treatment of lower community-acquired respiratory tract infections (LRTIs): from bacterial eradication to reduced lung inflammation and epithelial damage. European Review for Medical and Pharmacological Sciences 2014; 18:321-32.
  • 52. Sadaba B., Azanza J.R., Quetglas E.G., et al. Pharmacokinetic/pharmacodynamic serum and urine profile of cefditoren following single-dose and multiple twice- and thrice-daily regimens in healthy volunteers: a phase I study. Rev Esp Quimioter 2007; 20:51-60.
  • 53. Soriano F., Giménez M-J., Aguilar L. Cefditoren in upper and lower community-acquired respiratory tract infections. Drug Design, Development and Therapy 2011; 5:85-94.
  • 54. Cafini F., Yuste J., Gimйnez M.J., et al. Enhanced in vivo activity of cefditoren in pre-immunized mice against penicillin-resistant S. pneumoniae (serotypes 6B, 19F and 23F) in a sepsis model. PLoS One 2010; 5(8):e12041.
  • 55. Sevillano D., Aguilar L., Alou L., et al. High protein binding and cidal activity against penicillin-resistant S. pneumoniae: a cefditoren in vitro pharmacodynamic simulation. PLoS One 2008; 3(7):e2717.
  • 56. Alou L., Gimenez M.J., Sevillano D., et al. Are β-lactam breakpoints adequate to define non-susceptibility for all Haemophilus influenzae resistance phenotypes from a pharmacodynamic point of view? J Antimicrob Chemother 2007; 59:652-7.
  • 57. Canut A., Martin-Herrero J., Labora A., Maortua H. What are the most appropriate antibiotics for the treatment of acute exacerbation of chronic obstructive pulmonary disease? A therapeutic outcomes model. J Antimicrob Chemother 2007; 60:605-12.
  • 58. Granizo J.J., Gimenez M.J., Barberan J., Coronel P., Gimeno M., Aguilar L. Efficacy of cefditoren in the treatment of upper respiratory tract infections: a pooled analysis of six clinical trials. Rev Esp Quimioter 2008; 21:14-21.
  • 59. Casey J.R., Pichichero M.E. Meta-analysis of cephalosporins versus penicillin for treatment of group A streptococcal tonsillopharyngitis in adults. Clin Infect Dis 2004; 38:1526-34.
  • 60. Sevillano D., Aguilar L., Alou L., et al. Beta-lactam effects on mixed cultures of common respiratory isolates as an approach to treatment effects on nasopharyngeal bacterial population dynamics. PLoS One 2008; 3(12):e3846.
  • 61. Ozaki T., Nishimura N., Suzuki M, et al. Five-day oral cefditoren pivoxil versus 10-day oral amoxicillin for pediatric group A streptococcal pharyngotonsillitis. J Infect Chemother 2008; 14:213-218.
  • 62. Kikuta H., Shibata M., Nakata S., et al. Comparative study of 5-day and 10-day cefditoren pivoxil treatments for recurrent group A beta-hemolytic Streptococcus pharyngitis in children. Int J Pediatr 2009:863608.
  • 63. Poachanukoon O, Kitcharoensakkul M. Efficacy of cefditoren pivoxil and amoxicillin/clavulanate in the treatment of pediatric patients with acute bacterial rhinosinusitis in Thailand: a randomized, investigatorblinded, controlled trial. Clin Ther 2008; 30:1870-9.
  • 64. Granizo J.J., Gimйnez M.J., Barberбn J., Coronel P., Gimeno M., Aguilar L. The efficacy of cefditoren pivoxil in the treatment of lower respiratory tract infections, with a focus on the per-pathogen bacteriologic response in infections caused by Streptococcus pneumoniae and Haemophilus influenzae: a pooled analysis of seven clinical trials. Clin Ther 2006; 28:2061-9.
  • 65. Blasi F., Tarsia P., Mantero M., Morlacchi L.C., 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.
  • 66. Bucko A.D., Hunt B.J., Kidd S.L., et al. Randomized, double-blind, multicenter comparison of oral cefditoren 200 or 400 mg bid with either cefuroxime 250 mg bid or cefadroxil 500 mg bid for the treatment of uncomplicated skin and skin-structure infections. Clin Ther 2002; 24 (7): 1134-47.
  • 67. Granizo J.J., Aguilar L., Gimenez M.J., Coronel P., Gimeno M., Prieto J. Safety profile of cefditoren. A pooled analysis of data from clinical trials in community-acquired respiratory tract infections. Rev Esp Quimioter 2009; 22:57-61.
  • 68. Tucker R., Rhudy J., Hunt B., et al. Safety and efficacy of cefditoren in acute exacerbation of chronic bronchitis (AECB) [abstract no. 836 plus poster]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17-20; Toronto, 495.
  • 69. Henry D.C., Poling T.L., Bettis R.B., et al. A doubleblind, randomized study of cefditoren vs cefuroxime for AECB. J Respir Dis 2001; 22 (8 Suppl.):69-74.
  • 70. Fogarty C.M., Cyganowski M., Palo W.A., et al. A comparison of cefditoren pivoxil and amoxicillin/clavulanate in the treatment of community-acquired pneumonia: a multicenter, prospective, randomized, investigatorblinded, parallel-group study. Clin Ther 2002; 24(11): 1854-70.
  • 71. van Zyl L., le Roux J.G., LaFata J.A., et al. Cefditoren pivoxil versus cefpodoxime proxetil for communityacquired pneumonia: results of a multicenter, prospective, randomized, double-blind study. Clin Ther 2002; 24(11): 1840-53.
  • 72. Gooch W., Marsh D., Stickler T., et al. Cefditoren is safe and effective treatment for streptococcal pharyngitis [abstract no. 837 plus poster]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17-20; Toronto, 495.
Views
0 Abstract
0 PDF
0 Crossref citations
Shared