Telavancin
versus Vancomycin in Hospital-acquired pneumonia due to gram positive pathogens
Clin Infect Dis. 2011 January 1; 52(1): 31–40.
PMCID: PMC3060890
Ethan Rubinstein,
1 Tahaniyat Lalani,2,3 G. Ralph Corey,2,3 Zeina A. Kanafani,11 Esteban C. Nannini,12 Marcelo G. Rocha,15 Galia Rahav,16 Michael S. Niederman,4,5 Marin H. Kollef,6 Andrew F. Shorr,7 Patrick C. Lee,8 Arnold L. Lentnek,9 Carlos M. Luna,13 Jean-Yves Fagon,17 Antoni Torres,18 Michael M. Kitt,a Fredric C. Genter,10 Steven L. Barriere,10 H. David Friedland,a Martin E. Stryjewski,2,14 and for the ATTAIN Study Groupb
1 Tahaniyat Lalani,2,3 G. Ralph Corey,2,3 Zeina A. Kanafani,11 Esteban C. Nannini,12 Marcelo G. Rocha,15 Galia Rahav,16 Michael S. Niederman,4,5 Marin H. Kollef,6 Andrew F. Shorr,7 Patrick C. Lee,8 Arnold L. Lentnek,9 Carlos M. Luna,13 Jean-Yves Fagon,17 Antoni Torres,18 Michael M. Kitt,a Fredric C. Genter,10 Steven L. Barriere,10 H. David Friedland,a Martin E. Stryjewski,2,14 and for the ATTAIN Study Groupb
This article has been cited by other
articles in PMC.
Abstract
Hospital-acquired pneumonia (HAP) is
the second most common nosocomial infection and the leading cause of mortality
attributable to these critical infections [ 1– 3]. Staphylococcus aureus, particularly
methicillin-resistant S. aureus (MRSA), is now a major cause of HAP [ 4– 6]. Rates of clinical failure in patients with
HAP due to MRSA are high [ 7, 8]. Currently, only vancomycin and linezolid
are recommended for treatment of HAP due to MRSA [ 9]. Results from recent pneumonia trials with
new antibiotics active against MRSA have not been encouraging [ 10– 12]. Therefore, additional antistaphylococcal
agents for treatment of HAP are urgently needed.
Telavancin is a lipoglycopeptide antibacterial
agent exhibiting potent, concentration-dependent bactericidal effects via a
dual mechanism of action that combines inhibition of cell wall synthesis and
disruption of membrane barrier function [ 13– 15]. In vitro, telavancin is rapidly
bactericidal against clinically important gram-positive bacteria, including
MRSA, vancomycin-intermediate S. aureus, and penicillin-resistant S.
pneumoniae [ 13, 16, 17].
Telavancin penetrates well into the epithelial
lining fluid and alveolar macrophages of healthy subjects, achieving
concentrations up to 8-fold and 85-fold, respectively, above telavancin's
minimum inhibitory concentration (MIC) for 90% (MIC90) of MRSA strains (.5
μg/mL) [ 16, 18]. Unlike daptomycin (a cyclic lipopeptide),
telavancin remains active in vitro in the presence of pulmonary surfactant [ 16]. Telavancin is approved in the United States and Canada
The current studies were designed to
assess the clinical efficacy and safety of telavancin compared with vancomycin
in the treatment of HAP due to gram-positive organisms, with a focus on
infections due to MRSA. Partial results of these studies have been previously
reported.
METHODS
The Assessment of Telavancin for Treatment
of Hospital-Acquired Pneumonia (ATTAIN) studies were 2 identical randomized,
double-blind, comparator-controlled, parallel-group phase III trials, 0015 and
0019 (NCT00107952 and NCT00124020), with patients enrolled between January 2005
and June 2007. The institutional review board at each site approved the
protocol, and all patients or their authorized representatives provided written
informed consent.
Patient selection.
Male and nonpregnant female patients
aged ≥18 years were eligible for enrollment if they had pneumonia acquired
after 48 h in an inpatient acute or chronic care facility or that developed
within 7 days after being discharged. Patients were required to have ≥2 of the
following: cough, purulent sputum, auscultatory findings, dyspnea, tachypnea,
or hypoxemia; or identification of an organism consistent with a respiratory
pathogen isolated from respiratory tract or blood. In addition, patients were
also required to have ≥2 of the following: fever (temperature >38°C) or
hypothermia (rectal/core temperature <35°C); respiratory rate >30
breaths/min; pulse rate ≥120 beats/min; altered mental status; need for
mechanical ventilation; and white blood cell count >10,000 cells/mm3, <4500 cells/mm3, or >15% immature
neutrophils (band forms). All patients were required to have new or progressive
infiltrates, consolidation, with or without pleural effusion on chest
radiograph (or computed tomography), and an adequate respiratory specimen for
Gram stain and culture.
Patients were excluded if they had any
of the following: receipt of potentially effective systemic antibiotic therapy
for gram-positive pneumonia for >24 h immediately prior to randomization
(unless there was documented clinical failure after 3 days of therapy or if the
pathogen was resistant in vitro to previous treatment); only gram-negative
bacteria seen on Gram stain or culture; baseline QTc interval >500 msec,
uncompensated heart failure; absolute neutrophil count <500 cells/mm3; or pulmonary disease
that precludes evaluation of therapeutic response (eg, lung cancer, active
tuberculosis, cystic fibrosis, or granulomatous disease).
Randomization and treatment regimens.
The ATTAIN trials were
double-blinded studies in which patients were randomized (1:1) to receive
either intravenous (IV) telavancin at a dosage of 10 mg/kg every 24 h or
vancomycin at a dosage of 1 g IV every 12 h for 7–21 days. Randomization was
conducted through an interactive voice response system using permuted block
algorithm and stratifying by country group, presence of diabetes, and
ventilatory status. The vancomycin regimen could be monitored and adjusted
according to the institutional policy at each site but had to be performed such
that blinding was not compromised. The dose of telavancin was adjusted in
patients with creatinine clearance ≤50 mL/min. For patients with pneumonia due
to suspected or proven methicillin-susceptible S.
aureus (MSSA), a
switch to antistaphylococcal penicillin from vancomycin was permitted. In
patients with polymicrobial (mixed gram-positive/gram-negative) infection,
concomitant therapy with aztreonam or piperacillin-tazobactam was allowed.
Assessments.
Clinical assessments were performed at
baseline and daily throughout study treatment, at the end of therapy (EOT), and
at follow-up/test of cure visit (FU/TOC). Laboratory assessments were performed
every 3 days up to the EOT. FU/TOC assessment was conducted 7–14 days after
EOT.
Respiratory samples (invasive or noninvasive)
and 2 blood culture specimens were obtained at baseline for Gram stain and
culture [ 9]. Isolated pathogens were submitted to a
central laboratory for confirmation of identity and susceptibility testing [ 19].
Telavancin plasma samples for
pharmacokinetic analyses were obtained at some centers, as were vancomycin
trough levels, in accordance with site-specific procedures.
Efficacy and safety variables.
Clinical responses at
FU/TOC were defined as follows. Cure was defined as improvement or lack of
progression of baseline radiographic findings at EOT and resolution of signs
and symptoms of pneumonia at FU/TOC. Failure was defined as persistence or
progression of signs and symptoms or progression of radiological signs of
pneumonia at EOT; termination of study medications due to “lack of efficacy”
and initiation within 2 calendar days of a different potentially effective
antistaphylococcal medication; death on or after day 3 attributable to primary
infection; or relapsed infection at TOC after termination of study medications.
Indeterminate response was defined as the inability to determine outcome.
Adverse events (AEs), vital signs, electrocardiograms, and laboratory parameters
were also evaluated.
Analysis populations.
The all-treated (AT)
population included all randomized patients who received ≥1 dose of study
medication. The modified all-treated (MAT) population consisted of patients in
the AT population who had a respiratory pathogen identified from baseline
samples (or from blood cultures if no respiratory sample was positive). The
clinically evaluable (CE) population consisted of patients in the AT population
who were protocol-adherent or who died on or after study day 3, if death was
attributable to the HAP episode under study. The microbiologically evaluable
(ME) population consisted of CE patients who had a gram-positive respiratory
pathogen recovered from baseline respiratory specimens or blood cultures. The
safety population included patients who received ≥1 dose of study medication.
Statistical analyses.
The primary efficacy end point of each
study was clinical response at FU/TOC in the AT and CE populations. Failure at
EOT was carried forward to FU/TOC. Two-sided 95% confidence intervals (CIs)
were calculated on the difference in response rate; pooled-study CIs were
stratified on study. The primary efficacy end point was tested for the
noninferiority of telavancin compared with vancomycin in both the AT and CE
populations in each study, using a prespecified non-inferiority margin of 20%
and a 1-sided significance level of .025. Assuming that 35% of enrolled
patients would be in the CE group and that cure rates would be 60% in both
treatment groups, 312 enrolled patients per treatment arm would provide 109 CE
patients and statistical power of 86% to achieve noninferiority. A key
prespecified secondary objective was to perform a 2-study pooled analysis of
telavancin superiority compared with vancomycin treatment in patients with
pneumonia due to MRSA. Post hoc analyses of cure rates at FU/TOC visit by
baseline pathogen characteristics (methicillin resistance status, vancomycin
MIC, and evidence for mixed gram-negative/gram-positive infection) were also
performed; statistical inferential statements are not adjusted for multiple
comparisons.
Deaths through FU/TOC were summarized.
If there was no FU/TOC visit, any death reported to have occurred within 28
days after end of treatment was included in the analysis. Within this article,
results are presented from analysis of the pooled datasets from the 2 studies.
Primary efficacy results are also presented for each study separately.
RESULTS
Disposition of patients.
A total of 1532 patients from 274 study
sites in 38 countries were randomized (Figure 1). In all, 1503
patients received ≥1 dose of study medication (telavancin, n = 749; vancomycin,n =
754; AT population). The most common reasons for exclusion from the CE
population were indeterminate or missing responses at FU/TOC, receipt of
potentially effective nonstudy systemic antibiotics, and isolation of only
gram-negative bacteria ( Figure 1). The most common
reasons for missing or indeterminate responses at FU/TOC were patient death due
to causes other than HAP and presence of gram-negative pathogen only,
respectively.
Patient
disposition for studies 0015 and 0019. Patients could have >1 reason for exclusion
from either the clinically evaluable (CE) or microbiologically evaluable (ME)
populations. *Among those randomized to receive vancomycin, 20 patients had ...
Baseline and demographic
characteristics.
Baseline and demographic variables were
comparable between treatment groups ( Table 1). Patients aged ≥65
years accounted for more than one-half of those enrolled and treated in both
treatment groups. More than one-half of the patients were in intensive care
units at baseline. Common co-morbidities included diabetes mellitus, chronic
obstructive pulmonary disease, and acute and/or chronic renal failure. Almost
two-thirds of patients had multilobar infiltrates, and nearly one-third had
pleural effusions. Bacteremia was present in ∼6% of
patients. More than one-half of the patients received antibiotic therapy for
≥24 h prior to enrollment. Among these patients, the most common reasons allowing
enrollment were clinical failure despite prior antibiotic therapy and
development of pneumonia while receiving antibacterials for other indications.
Baseline
and Demographic Characteristics for the Pooled Studies All-Treated Population
Most of the respiratory sampling was via
expectorated sputum or endotracheal aspirates (particularly in intubated
patients), with <20% of patients undergoing more-invasive procedures ( Table 2). S.
aureuswas the most common gram-positive pathogen isolated from the
respiratory tract; the majority (60%) of S. aureus isolates were MRSA ( Table 2). Mixed infections
(ie, infections due to gram-positive and gram-negative pathogens) were present
in 27% of patients. The most common gram-negative pathogens were Pseudomonas
aeruginosa, Klebsiella pneumoniae, and Acinetobacter species.
Microbiological
Characteristics at Study Entry for the Pooled Studies Microbiologically
Evaluable Population
The MIC90 for both MRSA and MSSA was .5 μg/mL for telavancin and 1
μg/mL for vancomycin. The mean (± standard deviation [SD]) predose plasma
concentration (Ctrough) of telavancin for patients in the 2 studies were 10–12 μg/mL.
Telavancin mean peak plasma concentration was ∼70 μg/mL.
In those patients for whom >1 vancomycin serum trough level was obtained (n = 226), mean trough levels were ≥5 μg/mL in 94% (n =
212) and ≥10 μg/mL in 66% (n = 149) of patients.
Primary outcome measures.
Cure rates at FU/TOC in the 2 treatment
groups were similar in each study (Table 3). Results from
studies 0015 and 0019 each met the criterion for noninferiority of telavancin
compared with vancomycin. The 95% CI for the treatment difference between the 2
regimens from each study overlapped, supporting pooling of the data. Thus, cure
rates in the pooled AT population were 58.9% for telavancin and 59.5% for
vancomycin (95% CI for the difference, –5.6% to 4.3%), whereas in the pooled CE
patients, cure rates were 82.4% for telavancin and 80.7% for vancomycin (95% CI
for the difference, –4.3% to 7.7%). The most commonly listed reason for failure
at FU/TOC in AT and CE patients in both treatment groups was treatment failure
at EOT ( Table 4).
Cure Rates
for Hospital-Acquired Pneumonia at Follow-up/Test-of-Cure Visit
Reasons for
Treatment Failure at Follow-up/Test-of-Cure Visit for Pooled Studies
Secondary outcome measures.
In patients with pneumonia due to MRSA
with or without other pathogens, the clinical response at FU/TOC between the
treatment groups was similar ( Table 5). Cure rates were
higher in the telavancin group in patients with monomicrobial infection due to S.
aureus, and this was consistent for both patients with MRSA and
those with MSSA. Telavancin cure rates were also higher in patients infected
with S. aureus that
demonstrated a vancomycin MIC ≥1 μg/mL ( Table 5). Lower cure rates
in patients with mixed infections were observed in the telavancin group. In
patients with mixed infections who received adequate gram-negative coverage,
cure rates were similar between the 2 groups ( Table 5).
Cure Rates
at Follow-up/Test-of-Cure Visit by Baseline Pathogen for the Pooled
Microbiologically Evaluable Population
Safety analysis.
The overall incidence of AE was
comparable in the 2 groups ( Table 6). For study 0015, 80
(21.5%) of 372 telavancin-treated patients died, and 62 (16.6%) of 374
vancomycin-treated patients died (95% CI for the difference, –0.7% to 10.6%).
For study 0019, 70 (18.5%) of 379 telavancin-treated patients died, and 78
(20.6%) of 378 vancomycin-treated patients died (95% CI for the difference,
–7.8% to 3.5%).
Safety
parameters for the Pooled Studies Safety Population
Most common treatment-emergent AEs (TEAEs) in
both treatment groups were diarrhea, anemia, hypokalemia, constipation, and
renal impairment ( Table 6). The incidences of
serious AEs (SAEs) and TEAEs leading to discontinuation of study medication
were higher in the telavancin group (31% vs 26% and 8% vs 5%, respectively).
The most common SAEs in patients receiving telavancin and those receiving
vancomycin were septic shock (4% vs 4%), respiratory failure (3% vs 3%), and
multiorgan failure (3% vs 2%). The most frequently reported AE leading to study
medication discontinuation was acute renal failure (1.2%) in telavancin-treated
patients and septic shock (0.7%) in vancomycin-treated patients.
Potentially clinically significant increases
in serum creatinine levels (>50% increase from baseline and a maximum value
>1.5 mg/dL) were more common in the telavancin group than in the vancomycin
group (16% vs 10%). Other than creatinine level increases, the most common
abnormalities in both treatment groups were anemia, abnormal serum potassium
levels, and hepatic enzyme abnormalities (Table 7). All of these abnormalities
occurred with similar frequencies in the 2 treatment groups.
Laboratory
Abnormalities in Patients with Normal Values
at Baseline for the Pooled Studies Safety Population
Prolongation of Fridericia-corrected QT
interval (QTcF) by >60 msec occurred in 8% and 7% of the telavancin-treated
and vancomycin-treated patients, respectively. A maximum QTcF interval value
>500 msec occurred in a similar proportion of patients (2%) in the 2 groups.
None of the patients experienced arrhythmias attributable to a prolonged QTcF
interval.
DISCUSSION
The results of the ATTAIN trials
reported herein demonstrate that telavancin has clinical response outcomes that
are noninferior to those of vancomycin in the treatment of patients with HAP
due to the gram-positive bacteria, such as S. aureus (MRSA and MSSA) and S.
pneumoniae. Importantly, these findings, which incorporate data for
more than 1500 patients from >250 sites around the world, are robust and
consistent across all efficacy populations.
The ATTAIN trials, which enrolled almost 300
ME patients with monomicrobial S. aureus pneumonia, demonstrated that
telavancin therapy achieved higher cure rates than did vancomycin therapy in
the group of patients with pneumonia due to S. aureus. Higher cure rates were also
observed in the telavancin group among patients infected with S.
aureus that had a
vancomycin MIC ≥1 mg/L.
Importantly, telavancin was effective in the
treatment of patients with pneumonia due to MRSA, as well as in the treatment
of those patients with pneumonia due to MSSA. The high cure rates obtained in
the telavancin group support the use of telavancin as empirical therapy for
suspected S. aureus pneumonia as well as its use as
targeted therapy for both MRSA and MSSA infections.
A lower cure rate was associated with
telavancin therapy in the subgroup of patients with mixed infections, although
the difference was not statistically significant. Because telavancin has no
activity against gram-negative pathogens, these findings could be a result of
inadequate gram-negative therapy. This is supported by the finding that, in the
subset of patients with mixed infections who received adequate gram-negative
coverage, cure rates were similar in the 2 treatment groups.
Although more patients in the telavancin group
experienced SAEs or had treatment discontinued due to an AE, compared with
patients in the vancomycin group, the incidences of most common AEs were
similar in the 2 treatment groups. Clinically significant increases in serum
creatinine level were more frequent among telavancin-treated patients. In the
majority of patients in both groups with significant creatinine increases, the
impairment in renal function had resolved or was resolving at the last
follow-up visit. The numbers of patients with QTcF interval prolongation >60
msec or those with absolute QTcF interval >500 msec were comparable between
the treatment groups. Death rates were higher for telavancin-treated patients
than they were for vancomycin-treated patients in study 0015, whereas the
opposite trend was seen in study 0019. Although the ATTAIN trials were not
optimally designed for a mortality end point, the differences observed in these
studies were not statistically significant.
The strengths of the ATTAIN trials should be
underscored. First, when the ATTAIN trials were conducted, the combined
populations of these identically designed trials provided, to our knowledge,
the largest cohort of patients studied to date for HAP. Similarly, to date, the S.
aureus and MRSA
subgroups are the largest such subgroups available of patients with HAP. Third,
the breadth and diversity of the patient population make the results
generalizable to many settings. Lastly, a significant proportion of patients
enrolled in these studies were critically ill.
These studies also have limitations. First,
the standard of care in much of the world for diagnosis of HAP does not include
semi-invasive diagnostic procedures (eg, bronchoalveolar lavage), and the
limited number of patients who underwent these procedures makes determination
of the exact etiology of HAP potentially less reliable than would otherwise be
the case. However, the noninvasive diagnostic techniques used in these studies
followed the guidelines of the American Thoracic Society and the Infectious
Diseases Society of America [ 9] and are supported by a large
ventilator-associated pneumonia study that demonstrated similar outcomes for
patients undergoing invasive or noninvasive diagnostic approaches [ 22]. Second, our comparator antibiotic
(vancomycin) has been cited as potentially inferior to linezolid for patients
with MRSA pneumonia. However, the results of the post hoc analysis of 2
previous studies of linezolid versus vancomycin are controversial [ 23]. As a result, vancomycin continues to be
commonly used to treat patients with HAP in whom MRSA infection is suspected or
identified [ 24]. Third, the vancomycin dosage was adjusted
in accordance with institutional policies. Although such policies differed
between sites, they reflect the real use of vancomycin during the time period
in which these studies were conducted. Despite the unresolved controversy
regarding the clinical value of determining serum levels of vancomycin, the
large majority of patients for whom vancomycin levels were obtained had mean
trough levels that were considered “adequate” (ie, 5–15 μg/mL) at the time the
studies were conducted. Baseline renal status, as well as co-morbidities known
to predispose patients to renal dysfunction, should be taken into consideration
before treatment is initiated. Renal function should be monitored in all
patients receiving telavancin.
In summary, the 2 large identically
designed, double-blinded, randomized ATTAIN trials demonstrate that telavancin
is effective in the treatment of patients with HAP caused by gram-positive
pathogens. In the overall population, telavancin has an acceptable risk profile
for the treatment of patients with HAP.
Members of the ATTAIN
Study Group
C-S. Abboud, N.
Abdullah, A. Allworth, J. Altclas, T. Amgott, A. D. Aquila, K. Ashutosh, J.W.
Baddley, C.X. Bai, A. Bajpai, I. Balik, M.I.C. Barker, M.G. Bayasi, C. Beltrán,
A.K. Bhattacharya, P. K. Bhattacharya, D. L. Bowton, J. Brodnan, U. Bucksteg,
J. Cardoso, Y. Castaing, C. Chahin, K. Chang, C. Charters, Y.H. Chen, J.
Cheníček, R. Chetambath, H.J. Choi, J.Y. Choi, N. Chowta, Y.C. Chuang, M.
Clavel, M. Confalonieri, G. Criner, D. Curcio, F. De Rozario, F. Della Corte,
G. Deng, S. Dhalla, A. Dhar, F. M. Díaz, R. H. Dretler, O. Dziublyk, J.
Edington, A. El Sohl, W. Flynn Jr., P. Fogarty, F. Fôret, J. Fratzia, C.
Freuler, C. Galletti, J.B. Garcia-Diaz, V. Gasparovic, M. J. Gehman, A. Germar,
A. Gerogianni, M. Gerson, D. Ghelani, M. Giannokou-Peftoulidou, M. Giladi, V.
Golin, R. Grinbaum, I. Gudelj, I. Gugila, J.B. Gupta, O. Hadjiiski, G.L. Hara,
M. Heiner, K. Holn, M. Hojman, C. H. Huang, S.C. Hwang, K. H. In, A. Itzhaki,
T. Janasková, M. Kaaki, T. Kavardzhiklieva, S. Keenan, G. Kekstas, A. Khoja,
W.J. Kim, Y.K. Kim, U. Kivistik, S.K. Kochar, J. Koirala, I. Koksal, A. Komnos,
F. Koura, J. Kraatz, L. Kucharski, I. Kuzman, J. LaForge, D. Lakey, Z. Lazic,
A. Leditschke, J-Y. Lefrant, F. Lewis, J. Lipman, S. Liu, H. Lopes, T. Louie,
C. Lovesio, J. Mador, M. Magaña, A.A. Mahayiddin, M. Makhviladze, I. Maia, J.
Malone-Lee, E. Martinez, H. Metev, H. Minkowitz, M. Mitic-Miliki, N.
Monogarova, B.C. Montaldo, M. C. Montalban, P. Montravers, E. Moore, P.
Mootsikapun, R.A. Mori, G. Nackaerts, V. Nayyar, R. Norviliene, P. O'Neill, I.
Oren, W. O'Riordan, A. Ortiz, A.H.D. Pacheco, H.K. Park, Y.S. Park, M.J. Park,
S. Peake, T. Pejcic, Y. Pesant, G. Philteos, G. Pittoni, V. Platikanov, J.
Plutinsky, I. Potasman, J.P. Pretorius, D. Pryluka, J. Pullman, R. Raz, N.M.
Razali, M. Riachy, C. Rodriguez, Y. Roldan, E. Romero, C. Rondina, R. Salazar,
J. Santiagual, M.K. Sarna, F.A. Sarubbi, P. Sepulveda, T. Sheftel, Y. Shehabi,
P. Shitrit, E. Shmelev, J. Showalter, R. Siebert, V. Simanenkov, G. Simmons, J.
Sirotiakova, V. Skerk, S. Song, H. Standiford, C. Stefanov, R. Stienecker, K.
Stock, M. Street, R. Tabukashvili, D. Talwar, A. Tamariz, C. Tanaseanu, A.
Timerman, T. Todisco, S. Towfigh, V. Tsvetkov, N. Tudoric, A. Valavicius, R.
Valentini, C. Van Dyk, H. Van Rensburg, G. Villamizar, J-L. Vincent, C. Walker,
G.F. Wang, J.H. Wang, L.S. Wang, K. Weiss, J. Welker, Z. Wen, L.A. Witty, C.
Wu, P. Wu, C.T. Yang, K-Y. Yang, L. Yashyna, S. Yi, S.J. Yong, V. Yovtchev, M.
M. Yusoff, T. Zhang, X. Zhou, R. Zimlichman, E. Zonova, and F. Zveibil.
Acknowledgments
Financial support.The research and
publication process was supported jointly by Theravance, Inc. and Astellas
Pharma Global Development, Inc.
Manuscript preparation.Theravance, Inc. (South San Francisco
Potential conflicts of interest.E.R. has served as a
consultant for Theravance, Inc., Astellas, Pfizer, Bayer, Wyeth, Merck, Atox,
Ortho-McNeill, and sanofi-aventis. G.R.C. has served as a consultant for
Theravance, Inc.; has received support from Cubist Pharmaceuticals and
Theravance, Inc.; and serves as a consultant for Cerexa, Merck, Pfizer, Cempra,
and Astellas. E.C.N. received honoraria from Theravance, Inc. and research
support from Astellas and Johnson & Johnson. M.G.R.
has received research support from Theravance, Inc., Hospira, Novartis, and
Chiron for conducting clinical trials. G.R. has received a research grant from
Pfizer. M.S.N. has served as a consultant and received honoraria from Pfizer,
Merck, Astra-Zeneca, Johnson & Johnson, Theravance, Inc., Schering-Plough,
and Nektar and had received research support from Nektar and Pfizer. M.H.K. has
received research support from Merck, Pfizer, and Astellas. A.F.S. has either
served as a consultant or investigator or has delivered promotional lectures
for Astellas, Theravance, Inc., Pfizer, Merck, Johnson & Johnson,
Boehringer Ingelheim, GSK, sanofi-aventis, Canyon and Medicine Comp. P.L. has
served as a consultant for Smiths Medical and received honoraria from Wyeth, King
Pharmaceutical, and Adolor Corporation. A.L.L. has received research support
from Ortho-McNeill, Cerexa, Targanta, Optimer, and Theravance, Inc. and has
received honoraria from Cubist Pharmaceuticals. C.M.L. has served as a
consultant and received honoraria from Pfizer, Merck, Astra-Zeneca, and Bayer
and has received independent research support from Pfizer. A.T. has served as a
speaker for Astellas, Novartis, and Bayer and has research support from Pfizer.
M.M.K. is a former employee of Theravance, Inc. F.C.G. is an employee of
Theravance, Inc. S.L.B. is an employee of Theravance, Inc. H.D.F. is a former
employee of Theravance, Inc. M.E.S. has served as a consultant for Theravance,
Inc. and Trius Therapeutics, has received honoraria from Astellas, and received
research support from Theravance, Inc.
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