A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections [Study ID Numbers: 3074A1-301-WW; ClinicalTrials.gov Identifier: NCT00081744]
María E Oliva, Arcot Rekha, Albert Yellin, Jacyr Pasternak, Maria Campos, Gilbert M Rose, Timothy Babinchak, Evelyn J Ellis-Grosse, Evan Loh, 301 Study Group, María E Oliva, Arcot Rekha, Albert Yellin, Jacyr Pasternak, Maria Campos, Gilbert M Rose, Timothy Babinchak, Evelyn J Ellis-Grosse, Evan Loh, 301 Study Group
Abstract
Background: Complicated intra-abdominal infections (cIAI) remain challenging to treat because of their polymicrobial etiology including multi-drug resistant bacteria. The efficacy and safety of tigecycline, an expanded broad-spectrum glycylcycline antibiotic, was compared with imipenem/cilastatin (IMI/CIS) in patients with cIAI.
Methods: A prospective, double-blind, multinational trial was conducted in which patients with cIAI randomly received intravenous (IV) tigecycline (100 mg initial dose, then 50 mg every 12 hours [q12h]) or IV IMI/CIS (500/500 mg q6h or adjusted for renal dysfunction) for 5 to14 days. Clinical response at the test-of-cure (TOC) visit (14-35 days after therapy) for microbiologically evaluable (ME) and microbiological modified intent-to-treat (m-mITT) populations were the co-primary efficacy endpoint populations.
Results: A total of 825 patients received >or= 1 dose of study drug. The primary diagnoses for the ME group were complicated appendicitis (59%), and intestinal (8.8%) and gastric/duodenal perforations (4.6%). For the ME group, clinical cure rates at TOC were 80.6% (199/247) for tigecycline versus 82.4% (210/255) for IMI/CIS (95% CI -8.4, 5.1 for non-inferiority tigecycline versus IMI/CIS). Corresponding clinical cure rates within the m-mITT population were 73.5% (227/309) for tigecycline versus 78.2% (244/312) for IMI/CIS (95% CI -11.0, 2.5). Nausea (31.0% tigecycline, 24.8% IMI/CIS [P = 0.052]), vomiting (25.7% tigecycline, 19.4% IMI/CIS [P = 0.037]), and diarrhea (21.3% tigecycline, 18.9% IMI/CIS [P = 0.435]) were the most frequently reported adverse events.
Conclusion: This study demonstrates that tigecycline is as efficacious as imipenem/cilastatin in the treatment of patients with cIAI.
Trial registration: ClinicalTrials.gov NCT00081744.
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References
- Solomkin JS, Mazuski JE, Baron EJ, Sawyer RG, Nathens AB, DiPiro JT, Buchman T, Dellinger EP, Jernigan J, Gorbach S, Chow AW, Bartlett J. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis. 2003;37:997–1005. doi: 10.1086/378702.
- Gorbach SL. Intraabdominal infections. Clin Infect Dis. 1993;17:961–5.
- Lorber B, Swenson RM. The bacteriology of intra-abdominal infections. Surg Clin North Am. 1975;55:1349–54.
- Burnett RJ, Haverstock DC, Dellinger EP, Reinhart HH, Bohnen JM, Rotstein OD, Vogel SB, Solomkin JS. Definition of the role of enterococcus in intraabdominal infection: analysis of a prospective randomized trial. Surgery. 1995;118:716–21.
- de Vera ME, Simmons RL. Antibiotic-resistant enterococci and the changing face of surgical infections. Arch Surg. 1996;131:338–42.
- Marshall JC, Innes M. Intensive care unit management of intra-abdominal infection. Crit Care Med. 2003;31:2228–37. doi: 10.1097/01.CCM.0000087326.59341.51.
- Krobot K, Yin D, Zhang Q, Sen S, Altendorf-Hofmann A, Scheele J, Sendt W. Effect of inappropriate initial empiric antibiotic therapy on outcome of patients with community-acquired intra-abdominal infections requiring surgery. Eur J Clin Microbiol Infect Dis. 2004;23:682–7. doi: 10.1007/s10096-004-1199-0.
- 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;43:738–44.
- 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. doi: 10.1016/S0732-8893(99)00092-9.
- 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;46:2595–601. doi: 10.1128/AAC.46.8.2595-2601.2002.
- 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;47:400–4. doi: 10.1128/AAC.47.1.400-404.2003.
- 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;38:177–9. doi: 10.1016/S0732-8893(00)00193-0.
- Boucher HW, Wennersten CB, Eliopoulos GM. In vitro activities of the glycylcycline GAR-936 against gram-positive bacteria. Antimicrob Agents Chemother. 2000;44:2225–9. doi: 10.1128/AAC.44.8.2225-2229.2000.
- 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;52:138–9. doi: 10.1093/jac/dkg289.
- Low DE, Kreiswirth BN, Weiss K, Willey BM. Activity of GAR-936 and other antimicrobial agents against North American isolates of Staphylococcus aureus. Int J Antimicrob Agents. 2002;20:220–2. doi: 10.1016/S0924-8579(02)00132-2.
- 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 beta-lactamases. Diagn Microbiol Infect Dis. 2001;40:173–7. doi: 10.1016/S0732-8893(01)00269-3.
- Murray JA, Wilson S, Klein S, Yellin A, Loh E. The clinical response to tigecycline in the treatment of complicated intra-abdominal infections in hospitalized patients. A phase 2, clinical trial [abstract] Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. 2003;43:416.
- Dartois N, Gioud-Paquet M, Ellis-Grosse EJ, Loh E. Tigecycline vs imipenem/cilastatin for treatment of complicated intra-abdominal infections [abstract] Presented at the 44th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy. 2004. Session #97, Control #3841, Presentation #L-992c.
- Henwood CJ, Gatward T, Warner M, et al. Antibiotic resistance among clinical isolates of Acinetobacter in the UK, and in vitro evaluation of tigecycline (GAR-936) J Antimicrob Chemother. 2002;49:479–87. doi: 10.1093/jac/49.3.479.
- Muralidharan G, Getsy J, Mayer P, Paty I, Micalizzi M, Speth J, Wester B, Mojaverian P. Pharmacokinetics (PK), safety and tolerability of GAR-936, a novel glycylcycline antibiotic, in healthy subjects [abstract] Presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1999;39:303.
- Muralidharan G, Mojaverian P, Micalizzi M, Raible DG, Troy SM. Effects of age and sex on single-dose pharmacokinetics of tigecycline in healthy subjects. Antimicrobial Agents and Chemotherapy. 2005;49:1656. doi: 10.1128/AAC.49.4.1656-1659.2005.
- Sesoko S, Umemura K, Nakashima M. Pharmacokinetics (PK), safety and tolerability of tigcycline (GAR-936) in healthy Japanese males [abstract] Presented at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. 2002;42:22.
- 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;26:704–14. doi: 10.1016/S0149-2918(04)90070-7.
- Troy SM, Mauralidharan G, Micalizzi M, Mojavarian P, Salacinski L, Raible D. The effects of renal disease on the pharmacokinetics of tigecycline (GAR-936) [abstract] Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. 2003. Poster A-22.
- Zhanel GG, Homenuik K, Nichol K, Noreddin A, Vercaigne L, Embil J, Gin A, Karlowsky JA, Hoban DJ. The glycylcyclines: a comparative review with the tetracyclines. Drugs. 2004;64:63–88.
Source: PubMed