Clinical TrialsSafety and efficacy of intravenous tigecycline in treatment of community-acquired pneumonia: results from a double-blind randomized phase 3 comparison study with levofloxacin☆,☆☆,★
Introduction
Community-acquired pneumonia (CAP) affects 6 million people in the United States every year (Colice et al., 2004). About 1.3 million (approximately 20%) of these patients are hospitalized with a primary diagnosis representing CAP International Classification of Diseases, 9th Revision, Clinical Modifications (ICD-9-CMs) 480-486 (National Center for Health Statistics, 2002), with an estimated economic burden exceeding $30 billion in hospitalization charges alone (Kollef et al., 2005) and an associated mortality rate of approximately 12% (Fine et al., 1996, Niederman et al., 2001).
The most common cause of CAP is Streptococcus pneumoniae (File Jr, 2006, Lauderdale et al., 2005, Leesik et al., 2006, Luna et al., 2000). Other bacterial causes include Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and “atypical” CAP pathogens (i.e., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila) (Almirall et al., 2000, Gutierrez et al., 2005, Huang et al., 2006, Leesik et al., 2006, Luna et al., 2000, Marrie et al., 1996, Saito et al., 2006, Thibodeau and Viera, 2004, Woodhead, 2002). Escalating rates of antibiotic resistance have resulted in increases in treatment failures and poorer medical outcomes for many CAP patients (Bonofiglio et al., 2005, Felmingham, 2004, File Jr, 2006, Fuller et al., 2005, Gordon et al., 2003, Reinert et al., 2005, Thornsberry et al., 2002, Whitney et al., 2000, Woodhead, 2002), and it is imperative that clinicians consider a variety of factors including the severity of clinical presentation, comorbidities, patient history, age, and local antibiotic resistance patterns before selecting an antimicrobial therapy. Current guidelines recommend that patients hospitalized in a non-intensive care unit (ICU) setting with CAP receive monotherapy with a fluoroquinolone, such as levofloxacin, or combination therapy of a β-lactam plus a macrolide (Mandell et al., 2007, Niederman et al., 2001, Woodhead et al., 2005).
Tigecycline, a 1st-in-class expanded broad-spectrum glycylcycline, exhibits potent in vitro antibacterial activity against many common and atypical CAP pathogens, including a number of multiple antibiotic-resistant pathogens (Bradford et al., 2005, Hoban et al., 2005). Tigecycline's ability to penetrate lung tissue suggests an effective antibacterial treatment for hospitalized patients with CAP (Conte et al., 2005). The present study, conducted in hospitalized patients with CAP, compared the efficacy and safety of intravenous (IV) tigecycline to IV levofloxacin.
Section snippets
Study design
This was a phase 3, multicenter, double-blind study conducted between June 2003 and July 2005 at 54 centers in 8 countries in North America, South America, and Mexico/Central America. Each center received approval from its institutional review board or independent ethics committee, and all patients provided written informed consent. This study was conducted in accordance with the guidelines for Good Clinical Practices and the ethical principles of the Declaration of Helsinki (World Medical
Results
Of the 442 patients screened, 17 patients failed to meet protocol requirements and were not randomized (Fig. 1). Patients were well matched with respect to demographic and baseline medical characteristics in the tigecycline and levofloxacin groups in the mITT (safety) population (Table 2). The total number of patients with Fine IV and Fine <IV scores was 77/418 (18.4%) and 340/418 (81.3%), respectively. Approximately 15% of patients had underlying chronic obstructive pulmonary disease (COPD),
Discussion
Over the past 2 decades, there have been dramatic increases in the frequency of antibiotic resistance among the bacterial pathogens that cause CAP. Resistance to β-lactams, macrolides, and trimethoprim–sulfamethoxazole among clinical isolates of S. pneumoniae continues to rise at a rapid pace worldwide (Leesik et al., 2006, Mendes et al., 2004, Reinert et al., 2005, Sahm et al., 2001), with indications that fluoroquinolone resistance among clinical strains may also be increasing (Reinert et
Acknowledgments
This study and analysis was sponsored by Wyeth Research, Collegeville, PA. The authors thank Dr Angela Bridy-Pappas from Wyeth Research for her professional writing support, Ms Amanda Godshall and Ms Carol Cyphers from Wyeth Research for their assistance in conducting the study, Ms Denise A. Sarkozy from Wyeth Research for her statistical support, and Mr Jeff Goodrich from Wyeth Research for his programming assistance.
They also thank the following tigecycline 308 study group investigators for
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2015, International Journal of Infectious DiseasesCitation Excerpt :The heterogeneities between studies were both small with no significant differences in the two study populations. Eight studies12–14,17,18,21,22,25 reported microbiological treatment success in microbiological mITT (m-mITT) populations of 2704 patients, and showed no significant differences between groups (OR = 0.91, 95% CI = 0.74 to 1.11, P=0.35) (shown in Figure 4). For microbiologically assessable (ME) populations reported in twelve studies12–19,21,22,24,25 including 2876 patients, the microbiological treatment success for tigecycline was numerically lower than that for the comparator group with no significant difference (OR = 0.94, 95% CI = 0.77 to 1.16, P=0.56) (shown in Figure 5).
Diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish society of infectious diseases and clinical microbiology
2015, Enfermedades Infecciosas y Microbiologia ClinicaCitation Excerpt :This difference was not found in other studies in patients with cIAI. Regarding the severity of the infections, most were moderate, and immunocompromised patients were excluded.221–231 Therefore, from the evidence provided by these studies it cannot be inferred that the efficacy of tigecycline in monotherapy would be the same in more severe infections.
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Drs Bergallo, Teglia, and de Wouters do not have any conflict of interest to disclose. Dr Oliva has had involvement with the following companies: Johnson and Johnson, Roemmers, and Wyeth. Dr Lentnek works for Wellstar Research, which has received research grants from Wyeth, Cubist, Johnson and Johnson PRI, Pfizer, Optimer, Theravance, Vertex, Tibotec, GSK, Genentech, Arpidia, and Romark; the grants were all directed to Wellstar Health System and not personally received. Drs Dukart and Mallick and Ms Cooper are full-time employees of Wyeth Pharmaceuticals, the manufacturer of Tygacil® (tigecycline for injection).
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This study was supported by Wyeth Research. Wyeth Pharmaceuticals is planning to submit these data to government agencies for consideration of a new indication for tigecycline. These data were presented, in part, at the 2006 Infectious Diseases Society of America Meeting in Toronto, Ontario. Wyeth Pharmaceuticals is planning to publish these data in combination with data from another trial as an integrated manuscript.
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Protocol: 3074A1-308; trial registration number: NCT00079885.