Clinical Trial
Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia

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Abstract

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

Introduction

Hospital-acquired pneumonia (HAP) is associated with significant rates of morbidity and mortality, increased health care expenditures, and substantial consumption of resources (Craven et al., 1991). Mortality related directly to HAP, the “attributable mortality”, has been estimated to be between 33% and 50% (Heyland et al., 1999). Delays in treatment have been associated with higher mortality rates that can be reduced by up to 60% with appropriate antimicrobial therapy (Celis and Torres, 1988, Rello et al., 2001).

To improve outcomes and reduce mortality resulting from hospital-acquired infections, the American Thoracic Society (2005) (ATS) and the Infectious Diseases Society of America have established guidelines for the management of HAP. The new guidelines embrace the trio of prevention, diagnosis, and prompt, appropriate (adequate doses), broad-spectrum initial antibiotic therapy that is active against both Gram-positive and Gram-negative organisms.

Tigecycline is the first commercially available member of the glycylcyclines, a new class of antimicrobial agents. In vitro, it is active against vancomycin-resistant Enterococcus, methicillin-resistant Staphylococcus aureus (MRSA), and many species of multidrug-resistant Gram-negative bacteria such as Acinetobacter baumannii and extended-spectrum β-lactamase (ESBL)–producing Klebsiella pneumoniae and Escherichia coli (Poulakou and Giamarellou, 2007).

The primary objective of this study was to compare the efficacy and safety of a tigecycline ± ceftazidime ± aminoglycoside regimen with that of an imipenem/cilastatin ± vancomycin ± aminoglycoside regimen to treat patients with HAP. Secondary objectives were to evaluate the microbiologic efficacy of tigecycline, to obtain in vitro susceptibility data on tigecycline for a range of bacteria that cause HAP, to compare health care utilization between treatment arms, and to determine the pharmacokinetic profile of tigecycline for patients with HAP.

The decision to evaluate the efficacy of tigecycline in the treatment of HAP was based on its spectrum of in vitro activity (Fritsche and Jones, 2004, Sader et al., 2005) and the results of previous studies in animals showing its efficacy in the treatment of pneumonia (Entenza and Moreillon, 2009). In an animal model of Legionnaires' disease, Edelstein et al. (2003) have shown that treatment with tigecycline is effective in preventing death from otherwise fatal Legionella pneumophila pneumonia. Tigecycline was also shown to have in vivo activity in immunocompromised murine pneumonia models against A. baumannii and MRSA (Koomanachai et al., 2009a, Koomanachai et al., 2009b) and in combination with gentamicin against Pseudomonas aeruginosa (Mikels and Brown, 1999). Other indications of the potential of tigecycline as an effective treatment for HAP came from pharmacokinetic and pharmacodynamic studies, which indicated that tigecycline achieved acceptable concentrations in the lung (Conte et al., 2005, Rodvold et al., 2006). More recently, results from studies in humans have shown that tigecycline is safe and achieved clinical cure rates similar to levofloxacin in patients with community-acquired pneumonia (Tanaseanu et al., 2008). In addition, there are isolated case reports of good responses with tigecycline in patients with HAP (Curcio et al., 2009, Maclayton and Hall, 2007). The dose approved for other infections (i.e., 100 mg then 50 mg every 12 h) is predicted to have adequate serum concentrations for efficacy in HAP when used in combination with ceftazidime (Kuti et al., 2008).

Section snippets

Study design

This was a phase 3, randomized (1:1), double-blind trial of patients with HAP with 7 to 14 days of therapy and a test-of-cure (TOC) assessment 10 to 21 days after the last day of therapy. This trial was conducted in 138 sites in 31 countries between March 2004 and December 2006. Stratification at randomization was by diagnosis of ventilator-associated pneumonia (VAP) or non-VAP and Acute Physiologic and Chronic Health Evaluation (APACHE II) score (≤15 or >15) in order to ensure balance in

Results

Of the 979 patients screened, 34 were screen failures. A total of 945 patients comprised the randomized (ITT) population. A total of 934 patients (467 in each treatment group) were randomly assigned and received at least 1 dose of assigned treatment, comprising the modified intent-to-treat (mITT or safety) population. Of these, the CE subset of patients included 268 patients treated with tigecycline and 243 patients treated with imipenem/cilastatin (Fig. 1). The most common reasons for

Discussion

In the current study, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT population but not for the CE population. A statistically significant interaction was noted for the a priori stratification of non-VAP and VAP patients, with the initial analysis clearly indicating that the VAP subgroup behaved differently than the non-VAP subgroup. In non-VAP patients, tigecycline was noninferior to imipenem/cilastatin. Cure rates were 75.4% versus 81.3% in the CE

Conclusions

Overall, the study presented mixed results, with 1 of the coprimary efficacy end points being met and the other not being met. Various analyses indicate that the VAP subpopulation of patients drove the failure to meet 1 of the end points. It is not clear why VAP patients treated with tigecycline had lower cure rates compared with those who received imipenem/cilastatin, although a hypothesis is the lower tigecycline AUC/MIC that was observed, or why imipenem/cilastatin-treated patients had such

Acknowledgments

The statistical, programming, and managerial assistance of Jean Li Yan, Jeff Goodrich, Debbie Ruffo, Christina Auten, and Gaelle Amiard is greatly appreciated. Phil Vinall, a former Wyeth employee, assisted in the preparation of the preliminary draft of this article. Additional editorial support was provided by Upside endeavors, LLC (Sanatoga). This study was sponsored and funded by Wyeth Research, Collegeville, PA, which was acquired by Pfizer Inc in October 2009.

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