Clinical Trial Results
Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia,☆☆

https://doi.org/10.1016/j.diagmicrobio.2008.04.009Get rights and content

Abstract

Tigecycline (TGC), a glycylcycline, has expanded activity against Gram-positive and Gram-negative, anaerobic, and atypical bacteria. Two phase 3 studies were conducted. Hospitalized patients with community-acquired pneumonia (CAP) were randomized to intravenous (IV) TGC (100 mg followed by 50 mg bid) or IV levofloxacin (LEV) (500 mg bid). In 1 study, patients could be switched to oral LEV after at least 3 days intravenously. The coprimary efficacy end points were as follows: clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC). The secondary end points were as follows: microbiologic efficacy and susceptibility to TGC for CAP bacteria. Safety evaluations were included. Eight hundred ninety-one were patients screened: 846 mITT (TGC 424, LEV 422), 574 CE (TGC 282, LEV 292). Most patients had Fine Pneumonia Severity Index II to IV (80.7% TGC, 74.4% LEV, mITT). At TOC (CE), TGC cured 253/282 patients (89.7%) and LEV cured 252/292 patients (86.3%); the absolute difference of TGC-LEV was 3.4% (95% confidence interval [CI], −2.2 to 9.1, noninferior [P < 0.001]). In c-mITT, TGC cured 319/394 patients (81.0%) and LEV cured 321/403 patients (79.7%); the absolute difference of TGC-LEV was 1.3% (95% CI −4.5 to 7.1, noninferior [P < 0.001]). The drug-related adverse events (AEs) of nausea (20.8% TGC versus 6.6% LEV) and vomiting (13.2% TGC versus 3.3% LEV) were significantly higher in TGC; elevated alanine aminotransferase (2.8% TGC versus 7.3% LEV) and aspartate aminotransferase (2.6% TGC versus 6.9% LEV) were significantly higher in LEV. Discontinuations for AEs were low (TGC, 26 patients [6.1%]; LEV, 34 patients [8.1%]). TGC appeared safe and achieved cure rates similar to LEV in hospitalized patients with CAP.

Introduction

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality in adult populations (Almirall et al., 2000, File et al., 2004, Gutiérrez et al., 2005, Loh et al., 2004, O’Meara et al., 2005). The incidence and severity of CAP can be significant, especially in the elderly and immunocompromised (Gutiérrez et al., 2006, Kaplan and Angus, 2003, Ortqvist, 1990, Viegi et al., 2006). Every year, CAP affects 6 million people in the United States alone (Colice et al., 2004). Approximately 20% (1.1–1.3 million) of these patients are hospitalized (Niederman et al., 2001) at estimated charges of about $25 000 per hospitalization (Kollef et al., 2005) or over $30 billion in US hospitalization charges alone. Overall, approximately 12% of hospitalized patients die (File et al., 2004, Niederman et al., 2001). In patients with severe CAP requiring admission to the intensive care unit (ICU), mortality is around 30% (Bodí et al., 2005, Tejerina et al., 2005, Wilson and Ferguson, 2005, Woodhead et al., 2006).

The most common cause of CAP is Streptococcus pneumoniae (File, 2006, Lauderdale et al., 2005, Leesik et al., 2006, Luna et al., 2000). Other bacterial causes include Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, and the “atypical” CAP pathogens that include Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila (Almirall et al., 2000, Gutiérrez 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). Staphylococcus aureus and Gram-negative bacilli are not common causes, except in patients with severe CAP, who generally require admission to the ICU for treatment (Fine et al., 1996, Mandell et al., 2007, Niederman et al., 2001, Wilson and Ferguson, 2005, Woodhead et al., 2005).

Antibiotic treatment of CAP is usually empirically determined for adult patients treated in both hospital and outpatient settings. This is because specific pathogens are typically not identified at the time that antibiotic therapy is initiated. Retrospective epidemiologic studies have shown that pathogenic organisms were not isolated or identified in over 50% of patients exhibiting clinical signs and symptoms of CAP (Fine et al., 1996, Niederman et al., 2001, Woodhead et al., 2005). Furthermore, increasing rates of antibiotic resistance (most notably, penicillin, cephalosporin, and macrolide resistance) observed in bacteria that commonly cause CAP have resulted in increases in treatment failures and poorer medical outcomes for many patients with CAP (Bonofiglio et al., 2005, Felmingham, 2004, File, 2006, Fuller et al., 2005, Gordon et al., 2003, Reinert et al., 2005, Thornsberry et al., 2002, Whitney et al., 2000, Woodhead, 2002).

Tigecycline (TGC), a 1st-in-class glycylcycline, exhibits expanded broad spectrum in vitro activity against many Gram-positive, Gram-negative (except Pseudomonas aeruginosa), anaerobic, and atypical respiratory pathogens (Bradford et al., 2005, Hoban et al., 2005, Orth et al., 1999, Projan, 2000). To date, it has been approved by several regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, for the treatment of complicated intra-abdominal infections (cIAIs) and complicated skin and skin structure infections (cSSSIs). TGC's broad spectrum of activity coupled with its ability to effectively penetrate lung tissue suggests that it might be an effective antibacterial treatment for hospitalized patients with CAP (Conte et al., 2005).

An analysis of the combined results of 2 multinational, double-blind, phase 3 clinical studies that compared the efficacy and safety of intravenous (IV) TGC and IV levofloxacin (LEV) for the treatment of hospitalized adult patients with CAP (Dartois, 2006, Dukart, 2006) is reported here. In 1 of the studies, a switch to oral LEV was allowed after at least 3 days of IV dosing of study medications in subjects showing improvement in their signs and symptoms of pneumonia. LEV was chosen as the comparator antibiotic in this study because it is currently recommended by infectious disease authorities as 1 of the antibiotics of choice for CAP, and it is 1 of the most commonly prescribed antibiotics to treat patients with CAP (Bartlett et al., 2000, Mandell et al., 2007, Woodhead et al., 2005).

Section snippets

Study design

Two phase 3, multicenter, randomized, double-blind (3rd party unblinded) studies were conducted to compare the efficacy and safety of TGC with LEV in adult hospitalized patients with CAP. One study was conducted between June 2003 and July 2005 at 54 centers in 8 countries in North America, South America, and Mexico/Central America, and the other was conducted from January 2004 to January 2005 at 62 centers in 20 countries in Europe, Africa, and the Asia Pacific region. The protocols were

Patient disposition and baseline characteristics

Eight hundred forty-six of 891 patients who were screened were randomized to the study and received at least 1 dose of study medication (mITT population). Mean duration of therapy was approximately 10 days in each treatment arm. The demographic characteristics and baseline clinical assessments of patients in the safety population (mITT) are shown in Table 1, Table 2. Approximately half of these patients had Fine Pneumonia Severity Index scores of III to V (46.5% TGC; 47.2% LEV) (Table 3). In

Discussion

Over the past 2 decades, antimicrobial resistance has been steadily increasing in many Gram-positive and Gram-negative clinical isolates. Specifically, there have been dramatic increases in the frequency of antibiotic resistance among the bacterial pathogens that cause CAP. For example, resistance to β-lactams, macrolides, and trimethoprim–sulfamethoxazole among clinical isolates of S. pneumoniae continues to rise at a rapid pace on a worldwide basis (Leesik et al., 2006, Mendes et al., 2004,

Conclusions

TGC was efficacious, achieving clinical cure rates similar (noninferior) to LEV in these patients hospitalized with CAP, including achieving good cure rates in patients with comorbid disease, severity factors, and bacteremia. TGC appeared to be safe in this patient population, with a similar profile to that observed in patients with cIAI and cSSSI. As in other studies, the most frequently reported AEs with TGC were nausea and vomiting. Although, significantly, more TGC-treated patients than

Acknowledgments

This study and analysis was sponsored by Wyeth Research, Collegeville, PA. The authors thank Angela Bridy–Pappas from Wyeth Research for her professional writing support, Denise A. Sarkozy for her statistical support, and Jeff Goodrich for his programming assistance and Upside Endeavors for their editorial support.

The authors also thank the following tigecycline 308 and 313 study group investigators for their valuable involvement in this study: John Abernethy, Prabha Adhikari, C. Lynn, V.

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    ☆☆

    Drs. Tanaseanu, Bergallo, Teglia, Jasovich, and Oliva are investigators for this tigecycline study sponsored by Wyeth. Drs. Dukart, Dartois, and Gandjini and Ms. Cooper are employees of Wyeth.

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