Conceptos Categóricos

CARACTERISTICAS FARMACOLOGICAS DE UN NUEVO ANTIBIOTICO DE AMPLIO ESPECTRO

CARACTERISTICAS FARMACOLOGICAS DE UN NUEVO ANTIBIOTICO DE AMPLIO ESPECTRO

(especial para SIIC © Derechos reservados)
La tigeciclina, el primer antibiótico perteneciente a la familia de las glicilciclinas, es un aporte significativo al arsenal de fármacos eficaces contra los gérmenes aerobios grampositivos resistentes a múltiples drogas.
guay9.jpg Autor:
David Guay
Columnista Experto de SIIC

Institución:
Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota


Artículos publicados por David Guay
Recepción del artículo
17 de Febrero, 2006
Aprobación
7 de Marzo, 2006
Primera edición
30 de Octubre, 2006
Segunda edición, ampliada y corregida
1 de Octubre, 2007

Resumen
La tigeciclina es el derivado 9-t-butilciclamido de la tetraciclina minociclina. Es la primera glicilciclina en ser comercializada. Se piensa que la tigeciclina actúa a través de los mismos mecanismos que las tetraciclinas relacionadas estructuralmente, es decir la inhibición de la síntesis de proteínas al unirse a la subunidad 30S del ribosoma. Su actividad antibacteriana no está afectada por la presencia de los determinantes de resistencia a la tetraciclina, minociclina, penicilina, vancomicina, meticilina y los macrólidos, así como a las betalactamasas de amplio espectro. Su actividad es predominantemente bacteriostática y la resistencia está mediada por mecanismos que involucran las bombas de salida. A pesar de ser un antibiótico de amplio espectro, incluye en éste organismos de susceptibilidad intrínseca intermedia como Legionella, Ureaplasma, Proteus, Providencia, Morganella, Acinetobacter y especies de Bacteroides. Pseudomonas y las micobacterias atípicas son intrínsecamente resistentes. Disponible solamente para ser utilizada por vía intravenosa, la tigeciclina se concentra intracelularmente y penetra adecuadamente en varios compartimentos del tracto respiratorio y fluidos de las ampollas de la piel. El fármaco se elimina a través de un metabolismo hepático equilibrado, la secreción biliar y la excreción renal. El ajuste de dosis solamente es necesario en las alteraciones hepáticas graves (clase C de Child-Pugh; disminución de la dosis de mantenimiento del 50%). La tigeciclina demostró ser equivalente a los comparadores de referencia en el tratamiento de las infecciones intraabdominales complicadas, de la piel y sus anexos. Las náuseas y vómitos son los eventos adversos dependientes de la dosis más importantes, los cuales pueden disminuir parcialmente con las comidas. La única interacción farmacológica con importancia clínica potencial es con la warfarina, con la que la tigeciclina puede incrementar su respuesta hipoprotrombinémica al disminuir la depuración oral de la relación D-warfarina/L-warfarina en un 40%/23%. Si bien la introducción de la tigeciclina constituye un avance significativo en el tratamiento de las infecciones debidas a gérmenes aerobios grampositivos, se deben tener en cuenta dos aspectos importantes. Las náuseas y vómitos asociados a la dosis pueden comprometer seriamente la capacidad del médico para ajustar adecuadamente la posología del fármaco, lo cual, por otra parte, estimula la aparición y diseminación de los determinantes de resistencia vinculados a las bombas de salida hallados en varias especies (Salmonella, Proteus, Pseudomonas, etc.) y ser transferidos de un organismo a otro. Es esperable que estos factores no motiven que la tigeciclina muestre una breve vida como antimicrobiano en los humanos.

Palabras clave
tigeciclina, glicilciclina, minociclina


Artículo completo

(castellano)
Extensión:  +/-14.34 páginas impresas en papel A4
Exclusivo para suscriptores/assinantes

Abstract
Tigecycline is the 9-t-butylglycylamido derivative of the tetracycline minocycline. It is the first glycylcycline to be marketed. Tigecycline is thought to act via the same mechanism as the structurally-related tetracyclines, i.e. inhibition of bacterial protein synthesis by binding to the 30S subunit of the ribosome. Its antibacterial activity is unaffected by the presence of resistance determinants to tetracycline, minocycline, penicillin, vancomycin, methicillin, and the macrolides as well as extended-spectrum beta-lactamases. Its activity is bacteriostatic in nature and resistance is mediated primarily by efflux pump mechanisms. Despite broad-spectrum activity, organisms commonly of intrinsic intermediate susceptibility include Legionella, Ureaplasma, Proteus, Providencia, Morganella, Acinetobacter, and Bacteroides species. Pseudomonas and atypical mycobacteria are usually intrinsically resistant. Available only for IV use, tigecycline concentrates intracellularly and penetrates well into various respiratory tract compartments and skin blister fluid. Elimination occurs via balanced hepatic metabolism, biliary secretion, and renal excretion. Dosage regimen adjustment is needed only in severe hepatic impairment (Child-Pugh class C; 50% decrease in maintenance dose). Tigecycline has proven equivalent to standard comparators in the treatment of complicated intra-abdominal and skin and skin structure infections. The major dose-limiting adverse events are nausea and vomiting, which may be somewhat ameliorated by dosing on a full stomach. The only drug-drug interaction of potential clinical importance occurs with warfarin, wherein tigecycline may potentiate its hypoprothrombinemic response by reducing the oral clearance of S-warfarin/R-warfarin by means of 40/23 percent. Although tigecycline is an important advance in the therapy to infections due to multi-resistant gram-positive aerobes, two findings are of concern. Dose-related nausea and vomiting may seriously compromise the clinician's ability to use adequate doses of the drug. This may, in turn, promote the development and dissemination of efflux pump resistance determinants, which have already been found in a variety of species (Salmonella, Proteus, Pseudomonas, etc.) and can be passed from one organism to another. It is hoped that these factors will not result in tigecycline having but a brief life span as a useful antimicrobial in humans.

Key words
tigecycline, glycylcycline, minocycline


Full text
(english)
para suscriptores/ assinantes

Clasificación en siicsalud
Artículos originales > Expertos del Mundo >
página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Farmacología
Relacionadas: Bioquímica, Infectología, Medicina Farmacéutica



Comprar este artículo
Extensión: 14.34 páginas impresas en papel A4

file05.gif (1491 bytes) Artículos seleccionados para su compra



Enviar correspondencia a:
David Guay, Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, MN 55455, Weaver-Densford Hall 7-115C, 308 Harvard St. SE, Minneapolis, EE.UU.
Bibliografía del artículo
1. Bauer G, Berens C, Projan SJ, Hillen W. Comparison of tetracycline and tigecycline binding to ribosomes mapped by dimethylsulphate and drug-directed Fe2+ cleavage of 16S rRNA. J Antimicrob Chemother 2004; 53:592-9.
2. Bronson JJ, Barrett JF. Quinolone, everninomycin, glycylcycline, carbapenem, lipopeptide, and cephem antibacterials in clinical development. Curr Med Chem 2001; 8:1775-1793.
3. Bouchillon SK, Hoban DJ, Johnson BM, et al. In vitro evaluation of tigecycline and comparative agents in 3049 clinical isolates: 2001 to 2002. Diagn Microbiol Infect Dis 2005; 51:291-295.
4. Bogdanovitch T, Esel D, Kelly LM, et al. Antistaphylococcal activity of DX-619, a new des-F(6)-quinolone, compared to those of other agents. Antimicrob Agents Chemother 2005; 49:3325-3333.
5. Boucher HW, Wennersten CB, Eliopoulos GM. In vitro activities of glycylcycline GAR-936 against gram-positive bacteria. Antimicrob Agents Chemother 2000; 44:2225-2229.
6. Gales AC, Jones RN. Antimicrobial activity and spectrum of the new glycylcycline, GAR-936 tested against 1,203 recent clinical bacterial isolates. Diagn Microbiol Infect Dis 2000; 36:19-36.
7. Milatovic D, Schmitz FJ, Verhoef J, Fluit AC. Activities of the glycylcycline tigecycline (GAR-936) against 1,924 recent European clinical bacterial isolates. Antimicrob Agents Chemother 2003; 47:400-404.
8. Petersen PJ, Jacobus NV, Weiss WJ, Sum PE, Testa RT. In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Antimicrob Agents Chemother 1999; 43:738-744.
9. Petersen PJ, Bradford PA, Weiss WJ, Murphy TM, Sum PE, Projan SJ. In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant gram-positive pathogens. Antimicrob Agents Chemother 2002; 46:2595-2601.
10. Fritsche TR, Kirby JT, Jones RN. In vitro activity of tigecycline (GAR-936) tested against 11,859 recent clinical isolates associated with community-acquired respiratory tract and gram-positive cutaneous infections. Diagn Microbiol Infect Dis 2004; 49(3):201-9.
11. Patel R, Rouse MS, Piper KE, Steckelberg JM. In vitro activity of GAR-936 against vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. Diagn Microbiol Infect Dis 2000; 38:177-179.
12. Kitzis MD, Ly A, Goldstein FW. In vitro activities of tigecycline (GAR-936) against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother 2004; 48:366-367 (letter).
13. Fritsche TR, Sader HS, Stilwell MG, Dowzicky MJ, Jones RN. Potency and spectrum of tigecycline tested against an international collection of bacterial pathogens associated with skin and soft tissue infections (2000-2004). Diagn Microbiol Infect Dis 2005; 52:195-201.
14. Reynolds R, Potz N, Colman M, Williams A, Livermore D, MacGowan A. BSAC extended working party on bacteraemia resistance surveillance. Antimicrobial susceptibility of the pathogens of bacteraemia in the UK and Ireland 2001-2002: the BSAC Bacteraemia Resistance Surveillance Programme. J Antimicrob Chemother 2004; 53:1018-1032.
15. Cercenado E, Cercenado S, Gomez JA, Bouza E. In vitro activity of tigecycline (GAR-936), a novel glycylcycline, against vancomycin-resistant enterococci and staphylococci with diminished susceptibility to glycopeptides. J Antimicrob Chemother 2003; 52:138-139 (letter).
16. Betriu C, Culebras E, Rodriguez-Avial I, Gomez M, Sanchez BA, Picazo JJ. In vitro activities of tigecycline against erythromycin-resistant Streptococcus pyogenes and Streptococcus agalactiae: mechanisms of macrolide and tetracycline resistance. Antimicrob Agents Chemother 2004; 48:323-325.
17. Hoban DJ, Bouchillon SK, Johnson BM, Johnson JL, Dowzicky MJK. In vitro activity of tigecycline against 6792 gram-negative and gram-positive clinical isolates from the global Tigecycline Evaluation and Surveillance Trial (TEST Program, 2004). Diagn Microbiol Infect Dis 2005; 52:215-227.
18. Hoellman DB, Pankuch GA, Jacobs MR, Appelbaum PC. Antipneumococcal activities of GAR-936 (a new glycylcycline) compared to those of nine other agents against penicillin-susceptible and -resistant pneumococci. Antimicrob Agents Chemother 2000; 44:1085-1088.
19. Zhanel GG, Palatnick L, Nichol KA, Bellyou T, Low DE, Hoban DJ. Antimicrobial resistance in respiratory tract Streptococcus pneumoniae isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob Agents Chemother 2003; 47:1867-1874.
20. Betriu C, Rodriguez-Aviel I, Sanchez BA, Gomez M, Alvarez J, Picazo JJ, Spanish Group of Tigecycline. In vitro activities of tigecycline (GAR-936) against recently isolated clinical bacteria in Spain. Antimicrob Agents Chemother 2002; 46:892-895.
21. Biedenbach DJ, Beach ML, Jones RN. In vitro antimicrobial activity of GAR-936 tested against antibiotic-resistant gram-positive blood stream infection isolates and strains producing extended-spectrum ß-lactamases. Diagn Microbiol Infect Dis 2001; 40:173-177.
22. Fritsche TR, Sader HS, Stilwell MG, Dowzicky MJ, Jones RN. Antimicrobial activity of tigecycline tested against organisms causing community-acquired respiratory tract infection and nosocomial pneumonia. Diagn Microbiol Infect Dis 2005; 187-193.
23. Zhanel GG, Palatnick L, Nichol KA, Low DE, CROSS Study Group, Hoban DJ. Antimicrobial resistance in Haemophilus influenzae and Moraxella catarrhalis respiratory tract isolates: results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002. Antimicrob Agents Chemother 2003; 47:1875-1881.
24. Roblin PM, Hammerschlag MR. In vitro activity of GAR-936 against Chlamydia pneumoniae and Chlamydia trachomatis. Int J Antimicrob Agents 2000; 16:61-63.
25. Edelstein PH, Weiss WJ, Edelstein MA. Activities of tigecycline (GAR-936) against Legionella pneumophila in vitro and in guinea pigs with L. pneumophila pneumonia. Antimicrob Agents Chemother 2003; 47:533-540.
26. Kenny GE, Cartwright FD. Susceptibilities of Mycoplasma hominis, M. pneumoniae, and Ureaplasma urealyticum to GAR-936, dalfopristin, dirithromycin, evernimicin, gatifloxacin, linezolid, moxifloxacin, quinupristin-dalfopristin, and telithromycin compared to their susceptibilities to reference macrolides, tetracyclines, and quinolones. Antimicrob Agents Chemother 2001; 45:2604-2608.
27. Sader HS, Jones RN, Stilwell MG, Dowzicky MJ, Fritsche TR. Tigecycline activity testing against 26,474 bloodstrem infection isolates: a collection from 6 continents. Diagn Microbiol Infect Dis 2005; 52:181-186.
28. Sader HS, Jones RN, Dowzicky MJ, Fritsche TR. Antimicrobial activity of tigecycline tested against nosocomial bacterial pathogens from patients hospitalized in the intensive care unit. Diagn Microbiol Infect Dis 2005; 52:203-208.
29. Fritsche TR, Strabala PA, Sader HS, Dowzicky MJ, Jones RN. Activity of tigecycline tested against a global collection of Enterobacteriaceae, including tetracycline-resistant isolates. Diagn Microbiol Infect Dis 2005; 52:209-213.
30. Henwood CJ, Gatwood T, Warner M, James D, Stockdale MW, Spence RP, Towner KJ, Livermore DM, Woodford N. Antibiotic resistance among clinical isolates of Acinetobacter in the UK and in vitro evaluation of tigecycline (GAR-936). J Antimicrob Chemother 2002; 49:479-487.
31. Betriu C, Rodriguez-Avial I, Sanchez BA, Gomez M, Picazo JJ. Comparative in vitro activities of tigecycline (GAR-936) and other antimicrobial agents against Stenotrophomonas maltophilia. J Antimicrob Chemother 2002; 50:758-759 (letter).
32. Rhomberg PR, Jones RN. In vitro activity of 11 antimicrobial agents, including gatifloxacin and GAR 936, tested against clinical isolates of Mycobacterium marinum. Diagn Microbiol Infect Dis 2002; 42:145-147.
33. Wallace RJ Jr, Brown-Elliott BA, Crist CJ, Mann L, Wilson RW. Comparison of the in vitro activity of the glycylcycline tigecycline (formerly GAR-936) with those of tetracycline, minocycline, and doxycycline against isolates of nontuberculous mycobacteria. Antimicrob Agents Chemother 2002; 46:3164-3167.
34. Jacobus NV, McDermott LA, Ruthazer R, Snydman DR. In vitro activities of tigecycline against the Bacteroides fragilis group. Antimicrob Agents Chemother 2004; 48:1034-6.
35. Edlund C, Nord CE. In-vitro susceptibility of anaerobic bacteria to GAR-936, a new glycylcycline. Clin Microbiol Infect 2000; 6:159-163.
36. Betriu C, Culebras E, Gomez M, Rodriguez-Avail I, Picazo JJ. In vitro activity of tigecycline against Bacteroides species. J Antimicrob Chemother 2005; 56:349-352.
37. Goldstein EJ, Citron DM, Merriam CV, Warren Y, Tyrrell K. Comparative in vitro activities of GAR-936 against aerobic and anaerobic animal and human bite wound pathogens. Antimicrob Agents Chemother 2000; 44:2747-2751.
38. Cercenado E, Cercenado S, Bouza E. In vitro activities of tigecycline (GAR-936) and 12 other antimicrobial agents against Eikenella corrodens clinical isolates. Antimicrob Agents Chemother 2003; 47:2644-2645.
39. Biavasco F, Vignaroli C, Lupidi R, Manso E, Facinelli B, Varaldo PE. In vitro antibacterial activity of LY333328, a new semisynthetic glycopeptide. Antimicrob Agents Chemother 1997; 41:2165-2172.
40. Bozdogan B, Esel D, Whitener C, Browne FA, Appelbaum PC. Antibacterial susceptibility of a vancomycin-resistant Staphylococcus aureus strain isolated at Hershy Medical Center. J Antimicrob Chemother 2003; 52:864-868.
41. Murphy TM, Deitz JM, Petersen PJ, Mikels SM, Weiss WJ. Therapeutic efficacy of GAR-936, a novel glycylcycline, in a rat model of experimental endocarditis. Antimicrob Agents Chemother 2000; 44:3022-3027.
42. Van Ogtrop ML, Andes D, Stamstad TJ, Conklin B, Weiss WJ, Craig WA, Vesga O. In vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152, 288) against various gram-positive and gram-negative bacteria. Antimicrob Agents Chemother 2000; 44:943-949.
43. Mercier R-C, Kennedy C, Meadows C. Antimicrobial activity of tigecycline (GAR-936) against Enterococcus faecium and Staphylococcus aureus used alone and in combination. Pharmacotherapy 2002; 22:1517-1523.
44. Labthavikul P, Petersen PJ, Bradford PA. In vitro activity of tigecycline against Staphylococcus epidermidis growing in an adherent-cell biofilm model. Antimicrob Agents Chemother 2003; 47:3967-3969.
45. Ong CT, Babalola CP, Nightingale CH, Nicolau DP. Penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs). J Antimicrob Chemother 2005, online (doi:10.1093/jac/dki260).
46. Projan SJ. Preclinical pharmacology of GAR-936, a novel glycylcycline antibacterial agent. Pharmacotherapy 2000; 20(9 pt 2):219S-223S.
47. Anonymous. Tigecycline (Tygacid®) product information. Wyeth Pharmaceuticals Inc., Philadelphia, PA, June 2005.
48. Bradford PA, Petersen PJ, Young M, Jones CH, Tischler M, O'Connell J. Tigecycline MIC testing by broth dilution requires the use of fresh medium or addition of the biocatalytic oxygen-reducing reagent oxyvase to standardize the test method. Antimicrob Agents Chemother 2005; 49:3903-3909.
49. Petersen PJ, Bradford PA. Effect of medium age and supplementation with the biocatalytic oxygen-reducing reagent oxyvase on in vitro activities of tigecycline against recent clinical isolates. Antimicrob Agents Chemother 2005; 49:3910-3918.
50. Hope R, Warner M, Mushtaq S, Ward ME, Parsons T, Livermore DT. Effect of medium, type, age, and aeration on the MICs of tigecyline and classical tetracyclines. J Antimicrob Chemother 2005, online (doi:10.1093/jac/dki386).
51. Tuckman M, Petersen PJ, Projan SJ. Mutations in the interdomain loop region of the tet(A)(A) tetracycline resistance gene increase efflux of minocycline and glycylcycline. Microb Drug Resis 2000; 6:277-282.
52. McAleese F, Petersen P, Ruzin A, et al. A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory-derived Staphylococcus aureus mutants to tigecycline. Antimicrob Agents Chemother 2005; 49:1865-1871.
53. Visalli MA, Murphy E, Projan SJ, Bradford PA. AcrAB multidrug efflux pump is associated with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis. Antimicrob Agents Chemother 2003; 47:665-669.
54. Dean CR, Visalli MA, Projan SJ, Sum PE, Bradford PA. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob Agents Chemother 2003; 47:972-978.
55. Hirata T, Saito A, Nishino K, Tamura N, Yamaguchi A. Effects of efflux transporter genes on susceptibility of Escherichia coli to tigecycline (GAR-936). Antimicrob Agents Chemother. 2004; 48:2179-84.
56. Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother 2005; 49:220-229.
57. Sun HK, Ong CT, Umer A, et al. Pharmacokinetic profile of tigecycline in serum and skin blister fluid of healthy subjects after multiple intravenous administrations. Antimicrob Agents Chemother 2005; 49:1629-1632.
58. Conte JE Jr, Golden JA, Kelly MG, Zurlinden E. Steady-state serum and intrapulmonary pharmacokinetics and pharmacodynamics of tigecycline. Int J Antimicrob Agents 2005; 25:523-529.
59. Sesoko S, Umemura K, Nakashima M. Pharmacokinetics (PK), safety, and tolerability of tigecycline (GAR-936) in healthy Japanese males. Proceedings of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 27-30, 2002 (abstract A-1403).
60. Muralidharan G, Fruncillo RJ, Micalizzi M, Raible DG, Troy SM. Effects of age and sex on single-dose pharmacokinetics of tigecycline in healthy subjects. Antimicrob Agents Chemother 2005; 49:220-229.
61. Troy SM, Muralidharan G, Micalizzi M, Mojaverian P, Salacinski L, Raible D. The effect of renal disease on the pharmacokinetics of tigecycline (GAR-936). Proceedings of the 43rd Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 14-17, 2003 (abstract A-22).
62. Murray J, Wilson S, Klein S, Yellin A, Loh E. The clinical response to tigecycline in the treatment of complicated intra-abdominal infectious in hospitalized patients, a phase 2 clinical trial. Proceedings of the 43rd Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September 14-17, 2003 (abstract L-739).
63. Oliva ME, Rekha A, Yellin A, et al. A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections. BMC Infect Dis 2005; 5:88.
64. Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E, Tigecycline 301 and 306 Study Groups. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis 2005; 41:S354-S367.
65. Postier RG, Green SL, Klein SR, Ellis-Grosse EJ, Loh E. Tigecycline 200 Study Group. Results of a multicenter, randomized, open-label efficacy and safety study of two doses of tigecycline for complicated skin and skin-structure infections in hospitalized patients. Clin Ther 2004; 26:704-714.
66. Breedt J, Teras J, Gardovskis J, et al. Safety and efficacy of tigecyline in treatment of skin and skin structure infections: results of a double-blind phase 3 comparison study with vancomycin-aztreonam. Antimicrob Agents Chemother 2005; 49:4658-4666. 67. Ellis-Gross EJ, Babinchak T, Dartois N, Rose G, Loh E. Tigecycline 300 and 500 cSSSI Study Groups. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis 2005; 41:S341-S353.

 
 
 
 
 
 
 
 
 
 
 
 
Está expresamente prohibida la redistribución y la redifusión de todo o parte de los contenidos de la Sociedad Iberoamericana de Información Científica (SIIC) S.A. sin previo y expreso consentimiento de SIIC.
ua31618