Safety and efficacy of intravenous tigecycline in treatment of community-acquired pneumonia: results from a double-blind randomized phase 3 comparison study with levofloxacin

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Diagnostic Microbiology and Infectious Disease 63 (2009) 52 – 61 www.elsevier.com/locate/diagmicrobio

Clinical Trials

Safety and efficacy of intravenous tigecycline in treatment of community-acquired pneumonia: results from a double-blind randomized phase 3 comparison study with levofloxacin☆,☆☆,★ Carlos Bergalloa,⁎, Abel Jasovichb , Osvaldo Tegliac , Maria Eugenia Olivad , Arnold Lentneke , Luisa de Woutersf , Juan Carlos Zlocowskig , Gary Dukarth , Angel Cooperh , Rajiv Mallickh for the 308 Study Group a

Hospital Cordoba, Córdoba, Provincia de Córdoba, Argentina, 5000 Hospital Dr. Carlos Bocalandro, Buenos Aires, Provincia de Buenos Aires, Argentina, 1657 c Hospital Escuela “Eva Perón”, Granadero Baigorria, Provincia de Santa Fe, Argentina, 2152 d Hospital General “San Martín” Paraná, Paraná, Provincia de Entre Ríos, Argentina, 5300 e Wellstar Health Systems, Clinical Trials Office, Marietta, Georgia, USA, 30066 f Hospital Privado de Comunidad, Mar del Plata, Provincia de Buenos Aires, Argentina, 7600 g Hospital Privado Centro Medico de Cordoba S.A., Córdoba, Provincia de Córdoba, Argentina, 5016 h Wyeth Research, Collegeville, Pennsylvania, USA, 19426 Received 17 April 2008; accepted 3 September 2008 b

Abstract Tigecycline exhibits potent in vitro activity against many community-acquired pneumonia (CAP) pathogens, including antibioticresistant ones. Its spectrum of activity and ability to penetrate lung tissue suggest it may be effective for hospitalized CAP patients. Hospitalized CAP patients (n = 418) were randomized to receive intravenous (IV) tigecycline or levofloxacin. Patients could be switched to oral levofloxacin after receiving 6 or more doses of IV study medication. Therapy duration was 7 to 14 days. Coprimary efficacy end points were clinical responses in the clinically evaluable (CE: tigecycline, n = 138; levofloxacin, n = 156) and clinical modified intent-to-treat (c-mITT: tigecycline, n = 191; levofloxacin, n = 203) populations at test-of-cure (TOC). Safety was assessed in the mITT population (tigecycline, n = 208; levofloxacin, n = 210). Cure rates in tigecycline and levofloxacin groups were comparable in CE (90.6% versus 87.2%, respectively) and c-mITT (78% versus 77.8%, respectively) populations at TOC. Nausea and vomiting occurred in significantly more tigecycline-treated patients; elevated alanine aminotransferase and aspartate aminotransferase levels were reported in significantly more levofloxacin-treated patients. There were no significant differences in hospital length of stay, median

Abbreviation List: AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAP, community-acquired pneumonia; CE, clinically evaluable; CI, confidence interval; CLcr, creatinine clearance; c-mITT, clinical modified intent-to-treat; COPD, chronic obstructive pulmonary disease; DRAEs, drug-related adverse events; ECG, electrocardiogram; ICU, intensive care unit; ITT, intent-to-treat; IV, intravenous; LOS, length of stay; ME, microbiologically evaluable; MIC50, concentration of antibiotic that inhibited the growth of 50% of isolates; MIC90, concentration of antibiotic that inhibited the growth of 90% of isolates; m-mITT, microbiologic modified intent-to-treat; mITT, modified intent-to-treat; SAEs, serious adverse events; TdP, torsade de pointes; TOC, test-of-cure; WBC, white blood cell. ☆ 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). ☆☆ 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. ★ Protocol: 3074A1-308; trial registration number: NCT00079885. ⁎ Corresponding author. Tel.: +54-351-4349010; fax: +54-351-4513757. E-mail address: [email protected] (C. Bergallo). 0732-8893/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.diagmicrobio.2008.09.001

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duration of IV or oral antibiotic treatments, hospital readmissions, or number of patients switched to oral levofloxacin. Tigecycline was safe, effective, and noninferior to levofloxacin in hospitalized patients with CAP. © 2008 Published by Elsevier Inc. Keywords: Community-acquired pneumonia; Tigecycline; Glycylcycline; Levofloxacin; Fluoroquinolone; Efficacy; Safety

1. 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, 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 & 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, 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.

2. Methods 2.1. 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 Association Declaration of Helsinki, 1997). Patients were randomly assigned (1:1 ratio) to receive IV tigecycline or levofloxacin for a minimum of 3 days. An unblinded dispenser prepared all medications that were administered in a double-blind fashion. At randomization, patients were stratified on the basis of Fine Pneumonia Severity Index and geographic region. At hospital discharge, investigators could switch patients to oral levofloxacin openlabel antibiotic therapy to complete an antibacterial regimen that did not exceed 14 days (IV plus oral therapy). Patients randomly assigned to tigecycline were to receive an initial dose of 100 mg followed by 50 mg every 12 h thereafter. Patients randomly assigned to levofloxacin with creatinine clearance (CLcr) rates of at least 50 mL/min were to receive 500 mg every 24 h; for patients with renal insufficiency, dosage was modified according to the approved package insert. 2.2. Patients Adult patients (≥18 years old) hospitalized with clinical signs and symptoms of CAP for whom IV antibiotic treatment was indicated were eligible for study participation if they met inclusion/exclusion criteria (Table 1). Patients were allowed 1 dose (could be combination therapy) of a non-once daily antibiotic, or they could have failed a previous course of outpatient therapy with an oral antibiotic that was not a quinolone. After initial screening, patients were randomly assigned to treatment and constituted the intent-to-treat (ITT) population (Fig. 1). 2.3. Clinical assessments The clinical responses within the clinically evaluable (CE) and clinically modified ITT (c-mITT) populations at the test-of-cure (TOC) visit (between 7 and 23 days after

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C. Bergallo et al. / Diagnostic Microbiology and Infectious Disease 63 (2009) 52–61 Table 1 (continued)

Table 1 Patient entry criteria Inclusion criteria Men and women aged 18 years older

Hospitalized with CAP

IV antibiotic treatment indicated

Plus

Fever (within 24 h before study randomization), which was defined as oral temperature N38 °C/100.4 °F, axillary temperature N38.1 °C/100.6 °F, tympanic temperature N38.5 °C/101.2 °F, rectal temperature N39 °C/102.2 °F or hypothermia (rectal temperature b35 °C/95 °F) Plus At least 2 of the following signs and symptoms: Cough

Inclusion criteria Exclusion criteria

Primary lung cancer or any malignancy metastatic to the lungs Pregnant or breastfeeding women Female subjects of childbearing potential not using medically acceptable contraception or practicing abstinence throughout the study and for at least 1 month after the last dose of IV test article Known or suspected hypersensitivity to either study drug or to related compounds Failure to respond to levofloxacin or other quinolone antibiotics to treat this episode of CAP AST or ALT levels more than 10 times the upper limit of normal Total bilirubin level more than 3 times the upper limit of normal Neutropenia (neutrophil count b1 × 109/L or b1000/mm3) Calculated CLcr b20 mL/min Received any investigational drugs or used investigational devices within 4 weeks before the 1st dose of the study Had undergone ventilator therapy within 14 days before the onset of symptoms or required ventilator therapy at the time of study screening Used any drugs known to prolong the QT interval, including class Ia and III antiarrhythmics Required additional systemic antibacterial treatment

Concomitant conditions precluding an evaluation of a response or make it unlikely that the planned course of antibacterial therapy could be completed Hospitalization or residence in a long-term care facility for 14 or more days before the onset of symptoms Fine Pneumonia Severity Index score of V or treatment in an ICU required Concurrent hemodialysis, hemofiltration, peritoneal dialysis, or plasmapheresis Presence of clinically important central nervous system disease, including seizures or conditions that may predispose the patient to seizures, or severe psychiatric disorders that might prevent protocol compliance

Sustained shock at time of study randomization Risk factors for TdP, including hypokalemia; significant bradycardia or cardiomyopathy Known anatomic or pathologic bronchial obstruction or history of bronchiectasis or postobstructive pneumonia including end-stage COPD Immunosuppressive therapy

Production of purulent sputum or change in character of sputum consistent with bacterial infection Auscultatory findings of rales or Organ or bone marrow transplants evidence of pulmonary consolidation (dullness to percussion, bronchial breath sounds, or egophony) Dyspnea or tachypnea Known infection with human immunodeficiency virus, Pseudomonas aeruginosa, or Legionella Known or suspected pneumonia Elevated WBC (N10 000/mm3) caused by Pneumocystis carinii or N15% immature neutrophils regardless of WBC or leukopenia (b4500/mm3) Hypoxemia Known or suspected active tuberculosis Plus Cystic fibrosis Chest radiograph showing the presence of a new infiltrate within 48 h before initiation of study antibiotic therapya Known or suspected viral pneumonia unless also suspected or confirmed to have bacterial pneumonia

Exclusion criteria

a

The local reading of the chest X-ray was used to determine entry into the study, but presence of an infiltrate by a central reading (Bio-Imaging Technologies, Newtown, PA) was used to determine evaluability.

administration of the last dose of study medication) were the coprimary efficacy end points of the study. An investigator blinded to treatment categorized a patient's clinical response to therapy as cure, failure, or indeterminate. For c-mITT patients with available temperature records on therapy, time to defervescence (defined as time from randomization to the 1st day of attainment of oral temperature b37.9 °C on 2 consecutive days) was also assessed for each treatment group. 2.4. Microbiologic assessments Baseline bacterial cultures were taken from the primary site of infection, as were 2 sets of blood cultures obtained within 24 h before patients received the 1st IV dose of test medication. After collection, a Gram stain was performed on all respiratory specimens and interpreted by local microbiology laboratories. Diagnostic tests for infections due to Mycoplasma, Chlamydia, and Legionella were performed pretherapy. Aerobic and anaerobic clinical isolates were

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tested for susceptibility to tigecycline and levofloxacin using Kirby–Bauer disk-diffusion and broth microdilution methods. The isolates were subcultured and sent to a central laboratory (Covance Central Laboratory Services, Indianapolis, IN) for confirmation of isolate identity. Secondary efficacy variables included patient clinical response and microbiologic results at both the patient and pathogen level

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in the microbiologically evaluable (ME) and evaluable microbiologic mITT (m-mITT) patient populations at the TOC assessment. 2.5. Safety evaluation All patients who received at least 1 dose of study medication (mITT population) were evaluated for safety

Fig. 1. Number of subjects in each patient population. Intent-to-treat patients who received at least 1 dose of study drug were included in the mITT population. Patients in mITT population who met minimum disease criteria for CAP comprised c-mITT population. The m-mITT population consisted of patients in c-mITT population who had ≥1 isolate identified from sputum culture at baseline assessment. The CE population consisted of c-mITT patients who met the eligibility criteria: that is, received no more than 1 dose (single or combination therapy) of a non-once daily nonstudy antibacterial agent (except as noted for patients who failed a prior antibiotic regimen for this episode of CAP) before the 1st dose of study medication, did not receive more than 1 dose of a non-once daily concomitant systemic or aerosolized antibiotic treatment after their 1st dose of study medication (unless patient considered a treatment failure), received at least 3 days/6 doses of IV study medication and received between 80% and 120% of the total planned number of doses of IV study medication, unless considered a treatment failure (in which case received at least 2 days/4 doses of study medication), remained blinded, and had an assessment of cure or failure (not indeterminate) at TOC visit that occurred between 7 and 23 days after receiving last dose of study medication. Those patients included in the ME population were CE patients who had at least 1 identifiable baseline bacterial isolate(s) taken from the primary site of infection that was susceptible to both tigecycline and levofloxacin and who had a microbiologic response assigned, that is, eradication, persistence, or superinfection, or had serologic evidence of infection at TOC visit. Most common reasons for exclusion from the CE population included no baseline lung infiltrate (n = 24), N1 dose of prior antibiotic after baseline culture (n = 34), and no clinical evaluation at the TOC evaluation (n = 44). More tigecycline-treated subjects, as compared with levofloxacin-treated patients, did not have baseline infiltrates (tigecycline [17] versus levofloxacin [7]) and received greater than 1 dose of a prior antibiotic after baseline culture (tigecycline [21] versus levofloxacin [13]). An equal number of patients (22) from both treatment groups were excluded from the CE population due to the lack of a recorded clinical evaluation at the TOC assessment.

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readmission for ICU care, emergency room visits, or admission to nursing homes or long-term care facilities.

Table 2 Demographic and baseline characteristics of mITT population Characteristic

Tigecycline (n = 208) Levofloxacin (n = 210)

Age, mean (SD) (year) 55.49 (17.47) Sex, no. (%) of patients Male 112 (53.8) Female 96 (46.2) Ethnic origin, no. (%) White 127 (61.1) Hispanic 47 (22.6) Black 29 (13.9) Asian 3 (1.4) Other 2 (1.0) Weight, mean (SD) (kg) 74.90 (20.76) CLcr, mean (SD) (mL/min) 88.43 (57.23) Comorbidity conditions, no. (%) Diabetes mellitus 31 (14.9) COPD 35 (16.8) CHF 13 (6.3) Alcohol abuse 21 (10.1)

54.10 (19.79) 132 (62.9) 78 (37.1) 126 (60.0) 49 (23.3) 24 (11.4) 5 (2.4) 6 (2.9) 73.99 (20.45) 86.28 (55.30) 32 (15.2) 24 (11.4) 18 (8.6) 23 (11.0)

CHF = congestive heart failure.

(e.g., routine laboratory studies, 12-lead electrocardiogram [ECG] at baseline and day 3) and monitored for adverse events (AEs). Adverse events and serious AEs (SAEs) were recorded up to and including the TOC visit or 14 days after the last dose of study medication, whichever was greater. 2.6. Health outcomes assessment Resource utilization data collected for both treatment groups included length of stay (LOS), duration of IV antibiotic treatment, proportion of patients switched to oral therapy, duration of total antibiotic treatment (including postdischarge oral therapy), use of concomitant antibiotics, and LOS in the ICU. After hospital discharge and up through TOC, data were collected on any hospital readmission,

2.7. Statistical analysis The Clinical Biostatistics Department of Wyeth Research, Collegeville, PA, performed the statistical analyses. Categorical baseline demographic and medical variables were analyzed using a 2-sided Fisher's exact test performed at the 0.05 level of significance. Comparisons between treatment groups for continuous variables were assessed using an analysis of variance model with treatment as a factor. Between-group comparisons of AEs were analyzed by using a Fisher's exact test. For laboratory tests, vital signs, and ECG results, within-group changes from baseline were analyzed using a paired t test, and between-group comparisons were assessed using an analysis of covariance model that was adjusted for baseline values. Onset and duration of nausea and vomiting were analyzed using the log-rank test, and the relationship of concomitant medication to nausea and vomiting was analyzed using a Cochran–Mantel–Haenzel test. Time to defervescence was analyzed by the Kaplan– Meier approach using the log-rank test for differences in survival curves and, in terms of restricted means, with the restricted time limit set to the longest duration of observation of temperature for each group. Noninferiority of tigecycline was evaluated using a 2sided 95% confidence interval (CI) for the true difference in efficacy (tigecycline minus levofloxacin adjusted for stratification variables used at time of randomization). Noninferiority was concluded if the lower limit of the 2-sided 95% CI was greater than or equal to −15%. The method of Mehrotra and Railar (2000), which adjusts for stratification variables, was used when comparing the clinical and microbiologic responses of the 2 study medications.

Table 3 Clinical cure rates by study population at TOC visit Population

Tigecycline a

CE c-mITT ME Monomicrobialb Polymicrobialb m-mITT Monomicrobialb Polymicrobialb a

Levofloxacin a

n/N

% (95% CI)

n/N

% (95% CI)

125/138 149/191 70/75 52/56 17/18 84/100 64/78 18/20

90.6 (84.4 to 94.9) 78.0 (71.5 to 83.7) 93.3 (85.1 to 97.8) 92.9 (82.7 to 98.0) 94.4 (72.7 to 99.9) 84.0 (75.3 to 90.6) 82.1 (71.7 to 89.8) 90.0 (68.3 to 98.8)

136/156 158/203 84/93 61/66 22/26 95/115 70/86 23/27

87.2 (80.9 to 92.0) 77.8 (71.5 to 83.3) 90.3 (82.4 to 95.5) 92.4 (83.2 to 97.5) 84.6 (65.1 to 95.6) 82.6 (74.4 to 89.0) 81.4 (71.6 to 89.0) 85.2 (66.3 to 95.8)

TGC versus LEVO, % (95% CI for difference)

P value for test for noninferiority

P value for test for differences

3.4 (−4.4 to 11.2) 0.2 (−8.5 to 8.9) 3.0 (−6.4 to 12.5) 0.4 (−11.5 to 11.5) 9.8 (−16.1 to 30.8) 1.4 (−9.5 to 12.3) 0.7 (−12.3 to 13.2) 4.8 (−20.4 to 26.3)

b0.001 b0.001 b0.001

0.4570 1.0000 0.6676 2.3 (−6.2 to 10.8)c

0.0012

0.9286 1.8 (−8.3 to 11.9)c

n/N = number of cured patients/total number of patients. Patients were categorized as clinical cures if all signs and symptoms of pneumonia were improved or resolved, chest radiographs were improved or not worse, no further antibiotic therapy was required, and there were no new signs and symptoms of pneumonia. Patients were considered clinical failures if they had an inadequate response to therapy indicated by persistence or worsening in the signs and symptoms of pneumonia, initial improvement in clinical status followed by clinically important worsening before TOC, additional treatment with a nonstudy antibiotic for pneumonia, progression of chest radiograph abnormalities, death that resulted from pneumonia after day 2 of the study, or death resulting from a treatment-related AE. A patient was considered to have an indeterminate response if the patient was lost to follow-up or withdrew consent, died within 48 h after the 1st dose of study medication for any reason, or died after 48 h because of other reasons, including an infection other than pneumonia, as judged by the investigator. b Contaminants excluded. c Adjusted difference. TGC = Tigecycline, LEVO = Levofloxacin.

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Subpopulation (secondary) analyses were conducted to assess microbiologic responses at the patient and pathogen levels, clinical cure rates by baseline isolates, response rates for patients with monomicrobial versus polymicrobial infections, decreased antibiotic susceptibility, and individual pathogen susceptibility data (MIC50 and MIC90). All secondary analyses were conducted using adjusted differences between treatment groups at a 95% CI. For end points involving comparisons of tigecycline with levofloxacin with small sample sizes, the method of Wilson (1927) corrected for continuity was used. The method used to calculate 2-sided 95% CIs for a single proportion was the “exact” method of Clopper and Pearson (1934). With the planned sample size (n = 400) and an evaluability rate of ≥60%, the trial had a power of at least 90% to determine the noninferiority of tigecycline compared with levofloxacin. Unless otherwise specified, all statistical tests were performed at the 0.05 level of significance. A P value of b0.05 was considered significant. 3. 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 bIV scores was 77/418 (18.4%) and 340/418

Fig. 2. Time to defervescence: tigecycline versus levofloxacin. Time to defervescence was analyzed by the Kaplan–Meier approach, using the logrank test for differences in survival curves, as well as by restricted means, with the restricted time limit set to the longest duration of observation of temperature for each group. There were no statistically significant differences between the 2 treatment groups in terms of median time to defervescence (tigecycline, 2 days [interquartile (IQ) range, 2–3 days]; levofloxacin, 2 days [IQ, 2–4 days]; log-rank P = 0.097). There were also no statistically significant differences in terms of restricted means: mean (SE) for tigecycline, 3.26 (0.196) days; levofloxacin, 3.82 (0.282) days; P = 0.108.

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Table 4 Microbiologic response at TOC visit at isolate level: common CAP pathogens identified at baseline (ME population) Isolate

C. pneumoniae Documented Presumed H. influenzae Documented Presumed L. pneumophila Documented Presumed M. catarrhalis Documented Presumed M. pneumoniae Documented Presumed S. pneumoniae Documented Presumed a

Tigecycline

Levofloxacin

n/Na

% (95% CI)

n/N

% (95% CI)

13/14 0/13 13/13 6/6 0/6 6/6 7/7 0/7 7/7 3/3 0/3 3/3 13/14 0/13 13/13 39/41 1/39 38/39

92.9 (66.1–99.8) 0.0 100.0 100.0 (54.1–100.0) 0.0 100.0 100.0 (59.0–100.0) 0.0 100.0 100.0 (29.2–100.0) 0.0 100.0 92.9 (66.1–99.8) 0.0 100.0 95.1 (83.5–99.4) 2.6 97.4

15/16 0/15 15/15 7/9 0/7 7/7 1/1 0/1 1/1 2/3 0/2 2/2 22/24 0/22 22/22 58/63 1/58 57/58

93.8 (69.8–99.8) 0.0 100.0 77.8 (40.0–97.2) 0.0 100.0 100.0 (2.5–100.0) 0.0 100.0 66.7 (9.4–99.2) 0.0 100.0 91.7 (73.0–99.0) 0.0 100.0 92.1 (82.4–97.4) 1.7 98.3

n/N = number of cured patients/total number of patients.

(81.3%), respectively. Approximately 15% of patients had underlying chronic obstructive pulmonary disease (COPD), and a similar percentage had diabetes mellitus. In the ME population, approximately 15% of patients had S. pneumoniae bacteremia. 3.1. Clinical outcomes Clinical cure rates in the CE population were 90.6% for tigecycline and 87.2% for levofloxacin (difference, 3.4 [95% CI difference, −4.4 to 11.2]; Table 3). These differences were not significant (P = 0.4570), and tigecycline was determined to be statistically noninferior to levofloxacin (P b 0.001). Clinical cure rates at TOC in the c-mITT population were similar in both treatment groups (P = 1.0): 78% for tigecycline versus 77.8% for levofloxacin (difference, 0.2 [95% CI difference, −8.5 to 8.9]). Consistent with these findings, the efficacy of tigecycline in the c-mITT population met the statistical criteria of noninferiority to levofloxacin (P b 0.001, Table 3). Multiple subgroup analyses of clinical responses of patients in the CE patient population on the basis of age (b55 versus ≥55), gender, body mass index, or Fine Pneumonia Severity Index score showed similar results in clinical cure rates between the 2 treatment groups at the TOC assessment. For S. pneumoniae, the most commonly isolated CAP pathogen, clinical cure rates at the TOC visit in the ME population were 92.7% (95% CI, 80.1–98.5) for tigecycline versus 90.5% (95% CI, 80.4–96.4) for levofloxacin. Similarly, clinical cure rates for L. pneumophila were 100.0% (95% CI, 59.0–100.0) for tigecycline (7/7) and 100.0% (95% CI, 2.5–100.0) for levofloxacin (1/1). For tigecycline, the clinical cure rates for patients who had S. pneumoniae bacteremia (90.9%) were similar to those

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Table 5 MIC range and MIC50 and MIC90 values of common CAP pathogens from baseline isolates (ME population) Isolate

H. influenzae M. catarrhalis S. pneumoniae (non-PI, non-PR) S. pneumoniae (PISP) S. pneumoniae (PRSP)

Tigecycline

Levofloxacin

No. of Isolates

MIC range (μg/mL)

MIC50 (μg/mL)

MIC90 (μg/mL)

No. of Isolates

MIC Range (μg/mL)

MIC50 (μg/mL)

MIC90 (μg/mL)

15 6 45

0.06–1.0 0.06–0.12 0.03–0.12

0.25 NA 0.06

1.0 NA 0.06

15 6 45

0.12–0.12 0.12–0.12 0.5–1.0

0.12 NA 1.0

0.12 NA 1.0

2 4

0.06–0.06 0.06–0.12

NA NA

NA NA

2 4

0.5–1.0 0.5–1.0

NA NA

NA NA

MIC50 = minimum concentration of an antibiotic that inhibited the growth of 50% of the isolates; MIC90 = minimum concentration of an antibiotic that inhibited the growth of 90% of the isolates; NA = not determined; PI = penicillin intermediate; PR = penicillin resistant. MIC50 and MIC90 values are not valid for any pathogen with numbers fewer than 10.

of patients who did not have S. pneumoniae bacteremia (93.7%) at baseline. Although the cure rate for levofloxacintreated patients with S. pneumoniae bacteremia at baseline (76.9%) was somewhat lower than that for patients without S. pneumoniae bacteremia (92.4%), there were no significant differences between the efficacy of tigecycline as compared with levofloxacin for treatment of patients with or without S. pneumoniae bacteremia at baseline. The effect of switching from IV tigecycline or IV levofloxacin therapy to oral open-label levofloxacin treatment was also assessed at the TOC for patients in the CE population. There were no statistically significant differences between both treatment groups in the percentage of CE patients who switched to oral therapy (tigecycline, 89.9%; levofloxacin, 87.8%) or in the median duration of oral therapy (3.9 days for tigecycline versus 3.32 days for levofloxacin). There were no statistically significant differences in cure rates for patients who were switched to oral levofloxacin therapy. Secondary analyses of clinical responses at the TOC visits found no differences between the 2 treatment groups. Fig. 2 presents the Kaplan–Meier analysis of time to defervescence for each treatment group, which indicates no statistically significant differences. 3.2. Microbiologic outcomes In both the ME and m-mITT populations, there were no statistical differences in eradication rates, including monomicrobial, polymicrobial, persistence, or superinfection rates. Eradication rates at TOC for common CAP pathogens were not significantly different between tigecycline and levofloxacin in the ME (Table 4) and m-mITT patient populations (data not shown). The MIC range and MIC50 and MIC90 values for common baseline pathogens in the ME population are shown in Table 5. There was no evidence for the development of decreased susceptibility to tigecycline. 3.3. Health outcomes Healthcare resource utilization analyses on 394 subjects (tigecycline group, n = 191; levofloxacin group, n = 203) revealed no significant differences between the 2 treatment

groups for several key parameters (Table 6). In multivariate analyses (Table 7), prognostic factors identified to be predictive of longer duration of IV antibiotic treatment were presence of comorbid COPD (+0.76 days, P = 0.0126), treatment in a Latin American center (+1.20 days; P b 0.0001), and male gender (+0.45 days, P = 0.0266). Prognostic factors that emerged as predictive for longer hospital LOS included COPD (+1.20 days, P = 0.0247), a Fine Pneumonia Severity Index score equal to III (+0.93 days, P = 0.0282) or IV (+1.80 days, P = 0.0002), and treatment in a Latin American center (+0.97 days, P = 0.0099). In a separate analysis (not shown), switching to oral antibiotic therapy based on predefined clinical improvement criteria was associated with 2.89 days (P b 0.0001) shorter hospital LOS. 3.4. Safety and tolerability Tigecycline- and levofloxacin-treated patients in the mITT population received a median of 4 days of IV antibiotic treatment and 6 days of oral therapy. There were no significant differences between the 2 treatment groups in the duration of exposure to either study medication or in the Table 6 Health resource utilization: postdischarge outcomes among subjects hospitalized for CAP (c-mITT population) Resource

Tigecycline Levofloxacin P value (n = 191) (n = 203)

Overall mean length of hospital 6.6 stay (days) Mean duration of antibiotic 10.0 therapy (days) Mean duration of IV therapy (days) 4.6 Mean duration of PO therapy (days) 5.2 Hospital readmission (%) 2.6 Readmission for ICU care (%) 1.6 Postdischarge emergency room 0.5 visits (%) Additional nursing home care (%) 0 Patients who required concomitant 6.8 antibiotic therapy (%) Patients switched to oral antibacterial 81.2 therapy (%)

6.1

0.136

10.0

0.953

4.3 5.5 3.5 2.5 1.5

0.306 0.511 0.632 0.725 0.624

05 11.3

1.00 0.119

80.8

0.927

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number of treatment doses that were received by mITT patients. A total of 203 patients (48.6%) in both treatment groups in the mITT population (n = 418) reported 1 or more drug-related AE (DRAE). Table 8 shows the number of subjects who reported DRAEs with a frequency of at least 3% in either treatment group during both the IV and oral switch phases. Nausea and vomiting were the most commonly reported DRAEs in the tigecycline group, occurring in 16.3% and 12.0% of patients, respectively. Both nausea and vomiting occurred more frequently after tigecycline versus levofloxacin (5.7% and 1.9% of patients, respectively; P b 0.001), but the nausea and vomiting were generally categorized as mild to moderate in severity, and few tigecycline-treated patients discontinued study medication because of these events. The DRAEs that occurred significantly more frequently after levofloxacin treatment were increases in both alanine aminotransferase (ALT) (10.0%) and aspartate aminotransferase (AST) levels (10.0%). One patient randomized to tigecycline had an AE of Clostridium difficile-associated diarrhea during the follow-up period but had been switched to oral levofloxacin before this event. One patient randomized to levofloxacin had diarrhea for which she received metronidazole to treat what was noted as a C. difficile infection. Rates and reasons for premature discontinuations due to an AE and SAEs were not significantly Table 7 Multivariate regression models to identify prognostic factors for duration of IV antibiotic treatment and hospital LOS Covariate

Model 1: prognostic Model 2: prognostic factors for duration of IV factors for hospital LOS antibiotic treatment Parameter estimate (P value)

Treatment group Tigecycline (relative 0.20 (0.3124) to levofloxacin) Demographic factors Gender, Male 0.45 (0.0266) Region, Latin 1.20 (b0.0001) America Clinical characteristics Presence of comorbidity COPD 0.76 (0.0126) Neoplastic disease NS Medical history FINE Pneumonia Severity Index III NS IV NS

Parameter estimate (P value) 0.41 (0.2400)

NS 0.97 (0.0099)

1.20 (0.0247) -2.88 (0.0111)

0.93 (0.0282) 1.80 (0.0002)

Notes: (1) n = 394. (2) The reported parameter estimates reflect the estimated impact of the identified covariate in relation to its complementary/ reference level or absence of the characteristic; the numerical estimates are in terms of no. of days (of duration of IV antibiotic treatment or hospital LOS, in model 1 and 2, respectively). (3) Only covariates that were statistically significant in one of the outcome models (identified prognostic factors) from the multivariate stepwise regression models are shown, but the treatment comparison was included in both models, although not statistically significant. (4) NS = not statistically significant.

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Table 8 Drug-related AEs reported in ≥3% of patients in either treatment group in the mITT population Body system and AE

Any AE Body as a whole Headache Cardiovascular system Phlebitis Digestive systema Diarrhea Nauseaa Vomitinga Hemic and lymphatic system Anemia Eosinophilia Metabolic and nutritional Alkaline phosphatase increased Hypoproteinemia ALT levels increaseda AST levels increaseda Respiratory system Skin and appendages a

No. (%) of patients Tigecycline (n = 208)

Levofloxacin (n = 210)

107 (51.4) 26 (12.5) 13 (6.3) 20 (9.6) 15 (7.2) 54 (26.0) 17 (8.2) 34 (16.3) 25 (12.0) 22 (10.6) 7 (3.4) 7 (3.4) 22 (10.6) 4 (1.9) 6 (2.9) 8 (3.8) 7 (3.4) 5 (2.4) 7 (3.4)

96 (45.7) 18 (8.6) 10 (4.8) 25 (11.9) 16 (7.6) 25 (11.9) 9 (4.3) 12 (5.7) 4 (1.9) 22 (10.5) 7 (3.3) 11 (5.2) 34 (16.2) 8 (3.8) 9 (4.3) 21 (10.0) 21 (10.0) 7 (3.3) 3 (1.4)

Significant between-group difference (P ≤ 0.05).

different between the 2 treatment groups (data not shown). Eleven patients died during the study (5 tigecycline treated and 6 levofloxacin treated), but all deaths were considered by investigators to be unrelated to study medications. Differences between both treatment groups in mean change from baseline for serum chemistry tests, hematology and coagulation parameters, and vital signs were not clinically important. With respect to 12-lead ECG data, when the log-linear method was used to calculate the QTc interval, there were no statistically significant differences between tigecycline and levofloxacin. The median QTc change in tigecycline-treated patients at the final on-IV therapy assessment was −1.3 ms, with an upper limit of the 90% CI of 1.8 ms. Few subjects in either treatment group had QTc intervals greater than 500 ms, and those generally had significant underlying cardiovascular disease. 4. 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 al., 2005). This phase 3 multicenter trial compared the efficacy and safety of tigecycline monotherapy with that of levofloxacin.

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C. Bergallo et al. / Diagnostic Microbiology and Infectious Disease 63 (2009) 52–61

The efficacy of IV tigecycline was comparable with that of IV levofloxacin in hospitalized patients with CAP at the TOC visit across all predefined patient populations, and it was consistently effective against pathogens commonly associated with CAP. Multiple subgroup analyses revealed that tigecycline was similarly effective across a number of clinical and demographic attributes, Fine Pneumonia Severity Index scores, presence or absence of diabetes mellitus, monomicrobial versus polymicrobial infections, and presence or absence of bacteremia. There were no significant differences between the numbers of patients treated with IV tigecycline or IV levofloxacin who switched to oral levofloxacin therapy, nor were there any significant differences in the median duration of oral therapy for patients in either IV treatment group. For patients switched to oral therapy, the cure rates for both treatments were comparable. There were no significant differences between treatments concerning a variety of health outcomes assessments. In multivariate analyses, the Fine Pneumonia Severity Index emerged as predictive of longer LOS, consistent with other studies (Espana et al., 2003; Marras et al., 2000). In addition, comorbid COPD was identified as predictive of longer treatment duration and LOS, independent of other factors including pneumonia severity. This is consistent with previous studies (Marrie et al., 2000; Rello et al., 2006, Restrepo et al., 2006), reinforcing the suggested need to incorporate COPD in predictive severity-based indices for CAP outcomes (Restrepo et al., 2006). The results from this trial are consistent with those of another phase 3 study comparing tigecycline with levofloxacin (Dartois et al., 2006). Tigecycline showed efficacy against a broad spectrum of key CAP pathogens, including atypical CAP pathogens (M. pneumoniae, C. pneumoniae, and L. pneumophila), which is noteworthy because reports suggest that the number of CAP infections caused by these bacteria is growing (Marrie et al., 1996; Thibodeau & Viera, 2004). MIC90 values for tigecycline were uniformly low for typical respiratory pathogens. Clinical isolates of S. pneumoniae (including the antibiotic-resistant penicillin-resistant S. pneumoniae [PRSP] and penicillin-intermediate S. pneumoniae [PISP] strains) were susceptible to tigecycline. Tigecycline was shown to be safe and well tolerated. There was a significantly higher incidence of mild to moderate drug-related nausea and vomiting in tigecyclinetreated patients and a significantly greater incidence of drugrelated elevated ALT and AST levels in levofloxacin-treated patients. There was 1 reported event in a tigecycline-treated patient of “C. difficile positive” during the follow-up period. This patient had been switched to oral levofloxacin before the development of diarrhea. With respect to QTc mean change from baseline at the final on-IV therapy assessment, there were no significant differences between the 2 treatment groups by the log-linear method. The median QTc change in tigecycline-treated patients was −1.3 ms, with an upper limit of the CI of 1.8 ms.

Based upon the International Conference on Harmonisation (ICH) E14 guidance document, the observed low-amplitude changes are consistent with drugs that “do not appear to cause torsade de pointes (TdP)”, similar to what has been observed in other tigecycline studies. These results suggest that tigecycline is an efficacious and well-tolerated monotherapy, with comparable efficacy to levofloxacin, for treatment of hospitalized patients with CAP. Given that tigecycline dosing does not need to be modified for renal impairment or for mild to moderate hepatic impairment, and that tigecycline has low potential for drug–drug interactions, it represents a promising new antibiotic when empiric antimicrobial coverage is needed to treat hospitalized patients with CAP. 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 their valuable involvement in this study: John Abernethy, C. Lynn, V. Anderson, Charles P. Andrews, Rebeca Georgina Northland Areyuna, Cash Ralph Beechler, Salah Bibi, Markian R. Bochan, Maria Isabel Campos, Kevin M. Chan, Eduardo Rómulo Ticona Chavez, Roderick V. Clark, Francis L. Counselman, Larry I. Cowan, Per Erik Danielsson, Maria Inês Bueno de André Valery, João Adriano de Barros, Antonio Tarcisio de Faria Freire, Waldo Luis Leite Dias de Mattos, Albert G. Driver, John Embil, L. Christine Faulk, Thomas M. File Jr, Amalia Rodriguez French, Bruce Friedman, Carlos Cezar Fritscher, Catherine C. Gerrish, John A. Gezon, Philip A. Giordano, Donald R. Graham, Jon Allen Green, David Griffith, Doria Grimard, Colby H. Grossman, Arvind K. Gupta, Lloyd E. Hayes, Kennon Heard, Ernesto Julio Jakob, Robert A. Kearl, John J. Kelly, Noel Lampron, Iris Lorena Cazali Leal, Donald Levine, Daniel G. Lorch Jr, Wickliffe J. Many, Andrew McIvor, Nestor Rodolfo Sosa Montalvan, Gregory J. Moran, Maria Auxiliadora Carmo Moreira, Bangalore R. S. Murthy, William D. O'Riordan, Maria del Rayo Morfin Otero, Carlos Alberto Morales Paris, Robert L. Penn, Nora Patricia Quintero Perez, Anthony S. Ramage, Julio Ramirez, Carlos Rafael Seas Ramos, John F. Reinhardt, Milagros P. Reyes, Jane Rohlf, Guillermo M. Ruiz-Palacios y Santos, Christian Gerald Schrock, Stuart J. Simon, Priscilla B. Sioson, Harold C. Standiford, Carlos Ernesto Ferreira Starling, Roberto Stirbulov, Anthony M. Tello, Austin B. Thompson III, Fernando Cruz Mendo Urbina, Patricia Elena Fernandez Vasquez, Carlos Rodolfo Mejia Villatoro, Peter S. Vrooman Jr, Karl Weiss, Syed W.A. Zaidi.

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