Efficacy and safety of tigecycline monotherapy vs. imipenem/cilastatin in Chinese patients with complicated intra-abdominal infections: a randomized controlled trial

Zhangjing Chen, Jufang Wu, Yingyuan Zhang, Junming Wei, Xisheng Leng, Jianwei Bi, Rong Li, Lunan Yan, Zhiwei Quan, Xiaoping Chen, Yunsong Yu, Zhiyong Wu, Dawei Liu, Xiaochun Ma, Robert Maroko, Angel Cooper, Zhangjing Chen, Jufang Wu, Yingyuan Zhang, Junming Wei, Xisheng Leng, Jianwei Bi, Rong Li, Lunan Yan, Zhiwei Quan, Xiaoping Chen, Yunsong Yu, Zhiyong Wu, Dawei Liu, Xiaochun Ma, Robert Maroko, Angel Cooper

Abstract

Background: Tigecycline, a first-in-class broad-spectrum glycylcycline antibiotic, has broad-spectrum in vitro activity against bacteria commonly encountered in complicated intra-abdominal infections (cIAIs), including aerobic and facultative Gram-positive and Gram-negative bacteria and anaerobic bacteria. In the current trial, tigecycline was evaluated for safety and efficacy vs. imipenem/cilastatin in hospitalized Chinese patients with cIAIs.

Methods: In this phase 3, multicenter, open-label study, patients were randomly assigned to receive IV tigecycline or imipenem/cilastatin for </=2 weeks. The primary efficacy endpoints were clinical response at the test-of-cure visit (12-37 days after therapy) for the microbiologic modified intent-to-treat and microbiologically evaluable populations. Because the study was not powered to demonstrate non-inferiority between tigecycline and imipenem/cilastatin, no formal statistical analysis was performed. Two-sided 95% confidence intervals (CIs) were calculated for the response rates in each treatment group and for differences between treatment groups for descriptive purposes.

Results: One hundred ninety-nine patients received >/=1 dose of study drug and comprised the modified intent-to-treat population. In the microbiologically evaluable population, 86.5% (45 of 52) of tigecycline- and 97.9% (47 of 48) of imipenem/cilastatin-treated patients were cured at the test-of-cure assessment (12-37 days after therapy); in the microbiologic modified intent-to-treat population, cure rates were 81.7% (49 of 60) and 90.9% (50 of 55), respectively. The overall incidence of treatment-emergent adverse events was 80.4% for tigecycline vs. 53.9% after imipenem/cilastatin therapy (P < 0.001), primarily due to gastrointestinal-related events, especially nausea (21.6% vs. 3.9%; P < 0.001) and vomiting (12.4% vs. 2.0%; P = 0.005).

Conclusions: Clinical cure rates for tigecycline were consistent with those found in global cIAI studies. The overall safety profile was also consistent with that observed in global studies of tigecycline for treatment of cIAI, as well as that observed in analyses of Chinese patients in those studies; no novel trends were observed.

Trial registration: ClinicalTrials.gov NCT00136201.

Figures

Figure 1
Figure 1
Analysis populations and patient disposition: Tigecycline (TGC) vs. imipenem-cilastatin (I/C) in complicated intra-abdominal infections.
Figure 2
Figure 2
Tigecycline clinical cure rates compared to previous intra-abdominal studies (301, 306): (a) microbiologically evaluable (ME) and (b) microbiologic modified intent-to-treat (m-mITT) populations. Error bars indicate 95% confidence intervals, unweighted and calculated using the method of Clopper and Pearson.

References

    1. Mazuski JE, Sawyer RG, Nathens AB, DiPiro JT, Schein M, Kudsk KA, Yowler C. The Surgical Infection Society guidelines on antimicrobial therapy for intra-abdominal infections: evidence for the recommendations. Surg Infect (Larchmt) 2002;3(3):175–233. doi: 10.1089/109629602761624180.
    1. Solomkin JS, Mazuski JE, Baron EJ, Sawyer RG, Nathens AB, DiPiro JT, Buchman T, Dellinger EP, Jernigan J, Gorbach S. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis. 2003;37(8):997–1005. doi: 10.1086/378702.
    1. Weigelt JA. Empiric treatment options in the management of complicated intra-abdominal infections. Cleve Clin J Med. 2007;74(Suppl 4):S29–37. doi: 10.3949/ccjm.74.Suppl_4.S29.
    1. Nathens AB, Rotstein OD, Marshall JC. Tertiary peritonitis: clinical features of a complex nosocomial infection. World J Surg. 1998;22(2):158–163. doi: 10.1007/s002689900364.
    1. 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(9):682–687. doi: 10.1007/s10096-004-1199-0.
    1. Marshall JC, Innes M. Intensive care unit management of intra-abdominal infection. Crit Care Med. 2003;31(8):2228–2237. doi: 10.1097/01.CCM.0000087326.59341.51.
    1. Stein GE, Craig WA. Tigecycline: a critical analysis. Clin Infect Dis. 2006;43(4):518–524. doi: 10.1086/505494.
    1. Chopra I. New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors. Drug Resist Updat. 2002;5(3-4):119–125. doi: 10.1016/S1368-7646(02)00051-1.
    1. Gales AC, Sader HS, Fritsche TR. Tigecycline activity tested against 11808 bacterial pathogens recently collected from US medical centers. Diagn Microbiol Infect Dis. 2008;60(4):421–427.
    1. Hoban DJ, Bouchillon SK, Johnson BM, Johnson JL, Dowzicky MJ. 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(3):215–227. doi: 10.1016/j.diagmicrobio.2005.06.001.
    1. Zhanel GG, Karlowsky JA, Rubinstein E, Hoban DJ. Tigecycline: a novel glycylcycline antibiotic. Expert Rev Anti Infect Ther. 2006;4(1):9–25. doi: 10.1586/14787210.4.1.9.
    1. Castanheira M, Sader HS, Deshpande LM, Fritsche TR, Jones RN. Antimicrobial activities of tigecycline and other broad-spectrum antimicrobials tested against serine carbapenemase- and metallo-beta-lactamase-producing Enterobacteriaceae: report from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother. 2008;52(2):570–573. doi: 10.1128/AAC.01114-07.
    1. Draghi DC, Tench S, Dowzicky MJ, Sahm DF. Baseline in vitro activity of tigecycline among key bacterial pathogens exhibiting multidrug resistance. Chemotherapy. 2008;54(2):91–100. doi: 10.1159/000118660.
    1. 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(3):209–213. doi: 10.1016/j.diagmicrobio.2005.06.010.
    1. Meagher AK, Ambrose PG, Grasela TH, Ellis-Grosse EJ. The pharmacokinetic and pharmacodynamic profile of tigecycline. Clin Infect Dis. 2005;41(Suppl 5):S333–340. doi: 10.1086/431674.
    1. Babinchak T, Ellis-Grosse E, Dartois N, Rose GM, Loh E. 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(Suppl 5):S354–367. doi: 10.1086/431676.
    1. Gales AC, Jones RN, Andrade SS, Pereira AS, Sader HS. In vitro activity of tigecycline, a new glycylcycline, tested against 1,326 clinical bacterial strains isolated from Latin America. Braz J Infect Dis. 2005;9(5):348–356. doi: 10.1590/S1413-86702005000500001.
    1. 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(3):203–208. doi: 10.1016/j.diagmicrobio.2005.05.002.
    1. Tanaseanu C, Bergallo C, Teglia O, Jasovich A, Oliva ME, Dukart G, Dartois N, Cooper CA, Gandjini H, Mallick R. Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia. Diagn Microbiol Infect Dis. 2008;61(3):329–338. doi: 10.1016/j.diagmicrobio.2008.04.009.
    1. Fomin P, Beuran M, Gradauskas A, Barauskas G, Datsenko A, Dartois N, Ellis-Grosse E, Loh E. Three Hundred Six Study G. Tigecycline is efficacious in the treatment of complicated intra-abdominal infections. Int J Surg. 2005;3(1):35–47. doi: 10.1016/j.ijsu.2005.03.011.
    1. Breedt J, Teras J, Gardovskis J, Maritz FJ, Vaasna T, Ross DP, Gioud-Paquet M, Dartois N, Ellis-Grosse EJ, Loh E. Safety and efficacy of tigecycline 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(11):4658–4666. doi: 10.1128/AAC.49.11.4658-4666.2005.
    1. Sacchidanand S, Penn RL, Embil JM, Campos ME, Curcio D, Ellis-Grosse E, Loh E, Rose G. Efficacy and safety of tigecycline monotherapy compared with vancomycin plus aztreonam in patients with complicated skin and skin structure infections: Results from a phase 3, randomized, double-blind trial. Int J Infect Dis. 2005;9(5):251–261. doi: 10.1016/j.ijid.2005.05.003.
    1. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E. 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(Suppl 5):S341–353. doi: 10.1086/431675.
    1. 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(1):220–229. doi: 10.1128/AAC.49.1.220-229.2005.

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