Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE): Efficacy and Safety of Moxifloxacin Therapy versus That of Levofloxacin Therapy

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1 MAJOR ARTICLE Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE): Efficacy and Safety of Moxifloxacin Therapy versus That of Levofloxacin Therapy Antonio Anzueto, 1,2 Michael S. Niederman, 3 James Pearle, 4 Marcos I. Restrepo, 1,2 Albrecht Heyder, 5 and Shurjeel H. Choudhri, 6 for the Community-Acquired Pneumonia Recovery in the Elderly Study Group a 1 Department of Medicine, University of Texas Health Science Center, and 2 Veterans Evidence Based Research Dissemination and Implementation Center, Department of Medicine, South Texas Veterans Healthcare System, San Antonio, Texas; 3 Department of Medicine, Winthrop-University Hospital, Mineola, New York; 4 California Research Medical Group, Fullerton, California; 5 Carolina Research Specialists, Elizabeth City, North Carolina; and 6 Bayer Phaceuticals, West Haven, Connecticut Background. Limited prospective data are available for elderly patients with community-acquired pneumonia (CAP). This study aimed to determine the efficacy and safety of moxifloxacin versus that of levofloxacin for the treatment of CAP in hospitalized elderly patients (age, 65 years). Methods. We conducted a prospective, double-blind, randomized, controlled trial. Eligible patients were stratified by CAP severity before randomization to receive treatment with either intravenous/oral moxifloxacin (400 mg daily) or intravenous/oral levofloxacin (500 mg daily) for 7 14 days. Clinical response at test-of-cure (the primary efficacy end point was between days 5 and 21 after completion of therapy), and clinical response during therapy (between days 3 and 5 after the start of therapy) and bacteriologic response were secondary end points. Results. The safety population included 394 patients (195 in the moxifloxacin group and 199 in the levofloxacin group). The population eligible for clinical efficacy analysis (i.e., the clinically valid population) included 281 patients (141 in the moxifloxacin group and 140 in the levofloxacin group); 51.3% were male, and the mean age ( SD) was years. Cure rates at test-of-cure for the clinically valid population were 92.9% in the moxifloxacin and 87.9% in the levofloxacin (95% confidence interval [CI], 1.9 to 11.9; P p.2). Clinical recovery by days 3 5 after the start of treatment was 97.9% in the moxifloxacin vs. 90.0% in the levofloxacin (95% CI, ; P p.01). In the moxifloxacin group, cure rates were 92.6% for patients with mild or moderate CAP and 94.7% for patients with severe CAP, compared with cure rates of 88.6% and 84.6%, respectively, in the levofloxacin group ( P p not significant). Cure rates in the moxifloxacin were 90.0% for patients aged years and 94.5% for patients aged 75 years, compared with 85.0% and 90.0%, respectively, in the levofloxacin ( P p not significant). There were no statistically significant differences between the treatment groups with regard to drug-related adverse events. Conclusions. Intravenous/oral moxifloxacin therapy was efficacious and safe for hospitalized elderly patients with CAP, achieving 190% cure in all severity and age subgroups, and was associated with faster clinical recovery than intravenous/oral levofloxacin therapy, with a comparable safety profile. In the United States, community-acquired pneumonia (CAP) accounts for 15.6 million cases and 1 million hospitalizations annually [1]. A retrospective cohort Received 1 July 2005; accepted 23 August 2005; electronically published 22 November Presented in part: International Conference of the American Thoracic Society, San Diego, CA, May 2005 (abstract 2058). a Members of the study group are listed at the end of the text. Reprints or correspondence: Dr. Antonio Anzueto, 111E, 7400 Merton Minter Blvd., San Antonio, TX (Anzueto@uthscsa.edu). Clinical Infectious Diseases 2006; 42: by the Infectious Diseases Society of America. All rights reserved /2006/ $15.00 study of elderly persons (age, 65 years) estimated that nearly 915,900 CAP episodes occur annually in this population, with an incidence of 18.2 cases/1000 person-years for persons aged years, 27.9 cases/1000 person-years for those aged years, and 52.3 cases/ 1000 person-years for those aged 85 years [2]. Thus, 1 in 20 persons aged 85 years experiences a new CAP episode each year [2]. Approximately 40% of CAP episodes among elderly persons require hospitalization [2]. A mortality rate of 40% within 1 year after hospitalization has been reported [3]. Patients are frequently readmitted: in one study, 59% of surviving patients were readmitted Moxifloxacin vs. Levofloxacin for CAP in Elderly Patients CID 2006:42 (1 January) 73

2 within 18 months [4]. Accordingly, institution of appropriate antibiotic therapy is imperative for elderly patients, to prevent unnecessary morbidity and death [3, 5 8]. Updated CAP treatment guidelines recommend fluoroquinolone monotherapy or b-lactam plus macrolide combination therapy for hospitalized patients with CAP [9, 10]. However, no prospective clinical trials have been published that compare fluoroquinolones in hospitalized elderly patients with CAP. Thus, the primary purpose of this study was to compare the efficacy of sequential intravenous/oral moxifloxacin therapy with levofloxacin therapy in hospitalized elderly patients aged 65 years with CAP. A separate publication involving this same patient population and protocol describes the primary safety variable (i.e., cardiac adverse events) [11]. PATIENTS AND METHODS Study design and treatment. A prospective, randomized controlled, double-blind, double-dummy, comparative study was conducted from November 2002 to April 2004 at 47 study centers in the United States. The study was conducted in accordance with the Declaration of Helsinki, and each institution s internal review board approved the study protocol; written informed consent was obtained from each patient. After stratification by disease severity with the revised American Thoracic Society criteria (mild/moderate vs. severe) [10], patients were randomly assigned to receive either intravenous moxifloxacin, 400 mg once daily, or intravenous levofloxacin, 500 mg once daily, for 7 14 days. Patients were also assigned a Pneumonia Outcome Research Team pneumonia severity index score [12], although it was not used for stratification. For patients with a documented and/or a calculated creatinine clearance rate of ml/min, the intravenous dose of levofloxacin therapy was a 500-mg loading dose, followed by a dosage of 250 mg once daily for 7 14 days. Treatment with moxifloxacin did not require dosage adjustment for these patients. Patients could be switched to oral therapy at the investigator s discretion (moxifloxacin, 400 mg once daily, or levofloxacin, mg once daily) after 2 days of intravenous therapy if they demonstrated improvement during intravenous therapy, were afebrile for 8 h, and could tolerate oral food, fluids, and medications without vomiting or diarrhea. Both oral medications were encapsulated for blinding. Patient population. The trial population included hospitalized elderly patients (age, 65 years) with clinical signs and symptoms of CAP, radiologically confirmed evidence of a new and/or progressive infiltrate(s), a requirement for initial parenteral therapy, and at least 2 of the following conditions: productive cough with purulent and/or mucopurulent sputum ( 25 polymorphonuclear neutrophils per low-power field) or a change in sputum character (increased volume and/or purulence), dyspnea and/or tachypnea (respiratory rate of 120 breaths/min), rigors and/or chills, pleuritic chest pain, auscultatory findings of rales and/or crackles on pulmonary examination and/or evidence of pulmonary consolidation, fever (an oral temperature of 38 C [100.4 F], a rectal temperature of 39 C [102.2 F], or a tympanic temperature of 38.5 C [101.2 F]) or hypothermia (rectal or core temperature of!35 C [95.2 F]), and a WBC count of 10,000 cells/mm 3 or 15% immature neutrophils (bands; regardless of peripheral WBC count) or leukopenia (total WBC count of!4500 cells/mm 3 ). Patients with any of the following characteristics were excluded from the study: hospitalization for 148 h before pneumonia development, end-organ damage or shock (systolic blood pressure of!90 mm Hg and diastolic blood pressure of!60 mm Hg) with need for vasopressors for 14 h, need for mechanical ventilation, implanted cardiac defibrillator, significant bradycardia (heart rate of!50 beats/min), systemic antibacterial therapy for 124 h within 7 days of enrollment unless therapy failed after receiving 172 h of a nonfluoroquinolone antibiotic, mechanical endobronchial obstruction, known or suspected active tuberculosis or endemic fungal infection, neutropenia (neutrophil count of!1000 neutrophils/ml), chronic therapy (duration of 2 weeks) with immunosuppressant therapy (115 mg/day of systemic prednisone or equivalent), known HIV infection (CD4 cell count of!200 cells/mm 3 ), severe hepatic insufficiency (Child-Pugh classification of C), renal impairment (serum creatinine clearance rate of!20 ml/min), uncorrected hypokalemia, known prolongation of the corrected QT interval or use of class IA or class III antiarrhythmics, previous history of tendinopathy with quinolones, or known hypersensitivity to study medications. Clinical and bacteriologic evaluations. Clinical signs and symptoms were evaluated before treatment (within 48 h before receipt of the first dose of study drug), during treatment (between days 3 and 5 after the start of treatment), and at the test-of-cure visit (between days 5 and 21 after the end of therapy). Sputum samples were collected before study drug was started. Cultures were performed if Gram staining revealed 10 squamous epithelial cells per low-power field and 25 leukocytes per low-power field. Additional sputum specimens were obtained from patients with clinical failure. Blood specimens were obtained at enrollment, and if results of culture were positive, samples were obtained and cultured every 48 h until results were negative. A urinary antigen test for detection of Legionella pneumophila was performed. Clinical and bacteriologic outcome definitions. Clinical response at the test-of-cure visit (between days 5 and 21 after the end of therapy) was the primary efficacy outcome. Secondary efficacy outcomes included clinical response during therapy (between days 3 and 5 after the start of therapy) and bacteriologic response at the test-of-cure visit. Patients were considered to be eligible for the clinical efficacy 74 CID 2006:42 (1 January) Anzueto et al.

3 Figure 1. Patient flow in a clinical trial of the efficacy and safety of moxifloxacin versus that of levofloxacin in the treatment of hospitalized elderly patients with community-acquired pneumonia. analysis (i.e., for enrollment in the clinically valid population) if they met the eligibility criteria, received the study drug for 48 h (in cases of clinical failure) or for 5 days (in cases of clinical cure), received no other concomitant systemic antimicrobial therapy, had a test-of-cure clinical assessment that was not indeterminate, and had 80% adherence with study medication. Patients who met these criteria but discontinued receiving the study drug because of an adverse event were included in the efficacy analysis. Clinical response at the test-of-cure visit was defined as cure (disappearance of acute signs and symptoms related to the infection or sufficient improvement such that additional or alternative antimicrobial therapy was not required), failure (failure to respond or insufficient improvement of the signs and symptoms of infection such that additional antimicrobial therapy was required), or indeterminate. Clinical response at the during therapy visit (between days 3 and 5 after the start of therapy) was categorized as recovery (disappearance of acute signs and symptoms related to the infection or reduction in the severity and/or number of signs and symptoms of infection), failure (as defined above), or indeterminate. Patients who were in the clinically valid population and had a pathogen isolated from sputum or blood culture before treatment comprised the microbiologically valid population. Bacteriologic responses during therapy and at the test-of-cure visit were defined as eradication, presumed eradication (if no sputum specimen was available because of clinical success), persistence, presumed persistence (no sputum specimen was available for patients with clinical failure), or indeterminate. Superinfection was defined as the appearance of a new pathogen in patients with clinical failure. Safety and tolerability assessment. The safety analysis included patients who received at least 1 dose of study drug (intention-to-treat population). Adverse events were documented up to the test-of-cure visit using Medical Dictionary for Regulatory Activities (MedDra) terminology. Treatment-emergent adverse events (i.e., regardless of their relationship to study drug) and adverse reactions leading to premature discontinuation were recorded. Each adverse event was rated by the investigator on the basis of intensity (mild, moderate, or severe) and whether it was definitely, probably, or possibly related to the study drug. Serious adverse reactions were defined as those that were fatal, were life-threatening, required hospitalization, resulted in disability, or otherwise endangered the patient and were documented up to 30 days after receipt of the final dose of study drug. Serial blood and urine samples were collected throughout the study for routine hematologic, chemistry, and coagulation evaluations and for urinalysis. Moxifloxacin vs. Levofloxacin for CAP in Elderly Patients CID 2006:42 (1 January) 75

4 Table 1. Baseline demographic and medical characteristics of the clinically valid population in a clinical trial of the efficacy and safety of moxifloxacin versus levofloxacin for the treatment of hospitalized elderly patients with community-acquired pneumonia (CAP). Characteristic Moxifloxacin (n p 141) Levofloxacin (n p 140) P Male sex 69 (48.9) 71 (50.7).8 Race White 118 (83.7) 123 (87.9).5 Black 12 (8.5) 7 (5.0) Hispanic 11 (7.8) 9 (6.4) Asian 1 (0.7) Age, years Mean SD Range (64.5) 80 (57.1).2 Pneumonia severity index score (48.2) 57 (40.7) (29.1) 51 (36.4) 5 10 (7.1) 6 (4.3) Severe ATS CAP severity score a 19 (13.5) 26 (18.6).2 Nursing home residence 6 (4.3) 7 (5.0).7 Smoking history, mean pack-years Comorbidity Cardiac disorder Any 102 (72.3) 107 (76.4).5 Coronary artery disease 54 (38.3) 48 (34.3).6 Congestive heart failure 45 (31.9) 51 (36.4).5 Ischemic disorder 27 (19.1) 27 (19.3) 1.0 Respiratory disorder Any 97 (68.9) 111 (79.3).06 Bronchospasm and obstruction 87 (61.7) 96 (68.6).3 Parenchymal lung disorders 25 (17.7) 22 (15.7).8 Conditions associated with abnormal gas exchange 7 (5.0) 10 (7.1).6 Diabetes mellitus 40 (28.4) 38 (27.1).9 Estimated creatinine clearance rate!50 ml/min 69 (48.9) 61 (43.6).4 NOTE. Data are no. (%) of patients, unless otherwise indicated. a According to 2001 guidelines of the American Thoracic Society (ATS) [10]. Health resource utilization assessment. Data on the total duration of hospital stay, duration of intensive care unit (ICU) stay, total duration of antimicrobial therapy, and duration of intravenous therapy were collected at the test-of-cure visit. Statistical analysis. All statistical analyses were performed using SAS (SAS Institute) [13]. The primary efficacy objective was to show that moxifloxacin therapy was not inferior to levofloxacin therapy for the treatment of CAP, on the basis of clinical response at the test-of-cure visit for the clinically valid population. The power calculation for this end point was based on the Farrington-Manning method: assuming a clinical success rate of 90% and an eligibility of 70% for the enrolled subjects, a total of 400 enrolled patients provides 280 patients (400 patients 70%) in the clinically valid population, giving a power of 76% by using a D (critical difference) of 10% or a power of 90% by using a D of 15%. The Cochran-Mantel- Haenszel method was used to calculate 95% CIs [14]. Secondary efficacy end points included clinical outcome at other time points in the intention-to-treat and microbiologically valid populations, as well as bacteriologic outcomes. Logistic regression was performed to evaluate treatment effect on the primary dependent efficacy outcome variable (i.e., 76 CID 2006:42 (1 January) Anzueto et al.

5 Figure 2. Clinical outcomes for the clinically valid population: A, Clinical recovery during therapy (between days 3 and 5 after the start of treatment); *95% CI for difference, ( P p.01). B, Clinical cure at the test-of-cure visit (i.e., primary efficacy outcome); 95% CI for difference, 1.9 to 11.9 ( P p.2). clinical response at the test-of-cure visit) after adjusting for risk factors, including sex, race, age, pretreatment hospitalization history, pneumonia severity index score, switch from intravenous to oral treatment, sequence of intravenous dosing, smoking history, primary residence, presence of pathogen at baseline, body mass index, infection duration, aspiration pneumonia, and health status. Multiple logistic regression was performed with only those variables with P values of!.20. Treatment effect was evaluated after adjusting for other confounding factors in the regression model from the univariate analyses. Continuous independent variables were treated as continuous, with no collapsing done for the analysis. Demographic and clinical characteristics at baseline, adverse events, and laboratory data were summarized using descriptive statistics, and treatment groups were compared using 1-way analysis of variance for continuous variables or x 2 analysis for categorical data. RESULTS Patient disposition and demographic characteristics. Of 401 patients randomly assigned to receive study therapy, 7 received no study medication. Thus, the safety population included 394 patients (figure 1). The clinically valid population included 141 patients in the moxifloxacin group and 140 patients in the levofloxacin group. Baseline demographic and clinical characteristics for the clinically valid population are summarized in table 1 and were similar between the 2 treatment groups. The clinically valid population had a mean age ( SD) of years, with Figure 3. Clinical cure rates at the test-of-cure visit for the clinically valid population, stratified by community-acquired pneumonia (CAP) severity (A) and age (B). Moxifloxacin vs. Levofloxacin for CAP in Elderly Patients CID 2006:42 (1 January) 77

6 Table 2. Baseline positive culture results for and most common pathogens isolated from elderly patients who received moxifloxacin or levofloxacin for the treatment of community-acquired pneumonia (CAP). Variable No. (%) of patients Moxifloxacin (n p 21) a Levofloxacin (n p 30) Positive culture result, by culture site Respiratory 17 (81.0) 22 (73.3) Blood 5 (23.8) 8 (26.7) Pathogen isolated Streptococcus pneumoniae 7 (33.3) 10 (33.3) Haemophilus influenzae 3 (14.3) 9 (30) Staphylococcus aureus 3 (14.3) 7 (23.3) Pseudomonas aeruginosa b 2 (9.5) 5 (16.7) NOTE. All patients had negative results of urinary antigen tests for detection of Legionella pneumophila. a One patient had an organism isolated from cultures of respiratory and blood specimens. b Six strains were fluoroquinolone susceptible, and 1 strain from a patient in the levofloxacin was intermediate (moxifloxacin MIC, 4 mg/l). 60.9% of patients aged 75 years. Patients in this population had a mean number of 18.8 comorbidities (18.3 in the moxifloxacin group and 19.3 in the levofloxacin group; P p.67), and the mean number of pretreatment medications was 6.0. For the clinically valid population, the mean duration ( SD) of total antimicrobial therapy was days for the moxifloxacin and days for the levofloxacin ( P 1.8). The mean duration ( SD) of intravenous therapy was days for the moxifloxacin versus days for levofloxacin ( P p.7). The majority of patients were switched to oral therapy on day 3 or 4 after the start of therapy (93.6% in the moxifloxacin vs. 88.6% in the levofloxacin ; P p.2). Clinical outcomes. At the test-of-cure visit, the clinical cure rate (i.e., the primary efficacy outcome) for the clinically valid population was 92.9% for the moxifloxacin and 87.9% for the levofloxacin (95% CI, 1.9 to 11.9; P p.2) (figure 2). At the during treatment visit (between days 3 and 5 after the start of therapy) for the clinically valid population, 97.9% of patients in the moxifloxacin, compared with 90.0% of patients in the levofloxacin, had achieved clinical recovery (95% CI, ; P p.01) (figure 2). Univariate analysis identified the following risk factors as influences of clinical outcome (figure 3): for severe CAP, the rates of clinical cure were 94.7% in the moxifloxacin and 84.6% in the levofloxacin (95% CI, 0.12 to 0.32; P p.5); for patient age, the clinical cure rates for those aged years were 90.0% in the moxifloxacin and 85.0% in the levofloxacin (95% CI, 0.09 to 0.19; P p.6), and the rates for those aged 75 years were 94.5% and 90.0%, respectively (95% CI, 0.05 to 0.14; P p.4); and patients who were still receiving intravenous therapy at the test-of-cure visit had lower clinical cure rates (55.6% [5 of 9 patients] in the moxifloxacin vs. 50.0% [8 of 16 patients] in the levofloxacin ). Multiple regression analysis using various combinations of risk factors failed to show a statistically significant higher cure rate between treatment groups. Bacteriologic outcomes. Of the patients in the clinically valid population, 51 (18.1%) of 281 (21 [41.2%] in the moxifloxacin and 30 [58.8%] in the levofloxacin ) had 59 baseline pathogens identified in sputum or blood specimens and constituted the microbiologically valid population (table 2). Bacteriologic success (i.e., eradication or presumed eradication of the causal pathogen) at the test-of-cure visit was 81.0% in the moxifloxacin (17 of 21 patients) and 75.0% in the levofloxacin (21 of 28 patients) ( P p.9). The bacteriologic response was in agreement with the clinical response: clinical cure rates for the microbiologically valid population were 81.0% in the moxifloxacin (17 of 21 patients) versus 76.7% in the levofloxacin (23 of 30 patients) (95% CI, 0.22 to 0.31; P p.98). Safety and tolerability. The rate of treatment-emergent adverse events due to any cause was significantly higher in the moxifloxacin-treated patients ( P p.01 ) (table 3), although the rates of drug-related and serious adverse events were similar for both treatment s. There was no difference between treatments with regard to the rate of premature discontinuation owing to an adverse event; 17 (48.6%) of 35 of these events were considered to be drug related (10 in the moxifloxacin and 7 in the levofloxacin ). Serious adverse events were reported for 23% of patients in both treatment groups ( P p.9). No clinically significant differences between treatment groups were seen for clinical laboratory test values or vital signs. There was no difference in mortality between the 2 treatment groups ( P p.5), and the majority of deaths occurred 17 days after receipt of the final dose of study drug. Only 6 moxifloxacin- and 3 levofloxacin-treated patients died during therapy or within the first 7 days after therapy. None of the deaths were considered to be drug related, and all were determined by the investigators to be due to the patient s comorbid diseases. Health resource utilization. For the clinically valid population, the total duration of hospital stay ( SD) was days in the moxifloxacin and days in the levofloxacin ( P p.95), with a mean duration ( SD) of days and days, respectively, for hospital stay after the initiation of study drug treatment ( P p.95). For patients in the ICU, the total duration of hospital stay was similar between the treatment groups. There were no differences in health resource utilization between patients with positive versus those with negative results of pretherapy bacterial cultures. 78 CID 2006:42 (1 January) Anzueto et al.

7 Table 3. Overview of adverse events for hospitalized elderly patients eligible who received moxifloxacin or levofloxacin for the treatment of community-acquired pneumonia. Variable No. (%) of patients Moxifloxacin (n p 195) Levofloxacin (n p 199) Treatment-emergent adverse event 164 (84.1) 146 (73.4).01 Discontinued treatment due to adverse event 15 (7.7) 20 (10.1).5 Serious adverse event 46 (23.6) 45 (22.6).9 Death 15 (7.7) 11 (5.5).5 Any drug-related adverse event 51 (26.2) 45 (22.6).5 Drug-related adverse event reported by 11.5% of patients in either treatment group Diarrhea 11 (5.6) 10 (5.0) 1.0 Oral candidiasis 7 (3.6) 7 (3.5) 1.0 Nausea 3 (1.5) 4 (2.0) 1.0 Clostridium difficile infection/colitis 1 (0.5) 6 (3.0).1 Cardiac event 2 (1.0) 7 (3.5).2 Atrial fibrillation 0 3 (1.5) Ventricular tachycardia 1 (0.5) 1 (0.5) Acute myocardial infarction 0 1 (0.5) Atrial flutter 0 1 (0.5) Congestive heart failure 0 1 (0.5) Cardiorespiratory arrest 0 1 (0.5) Supraventricular tachycardia 1 (0.5) 0 Torsade de pointes 0 1 (0.5) Chest pain 0 1 (0.5) Increased heart rate 0 1 (0.5) P DISCUSSION In this prospective, randomized, double-blind trial involving hospitalized elderly patients with CAP, moxifloxacin-treated patients were more likely to have clinical improvement by treatment day 3 5 than were levofloxacin-treated patients. The overall clinical cure rate and bacteriologic success rates were similar between the 2 treatment groups. There was a higher incidence of adverse events due to any cause in the moxifloxacin group, although the incidence of drug-related adverse events was similar to that in the levofloxacin group. In subgroup analyses based on CAP severity and patient age, clinical cure rates in the moxifloxacin were consistently higher than, although not statistically significantly different from, those for levofloxacin. This trial included 394 elderly patients with a mean age ( SD) of years, 60.9% of whom were at least 75 years old. Most patients had concomitant comorbid conditions, including cardiac, gastrointestinal, chronic lung disease, and diabetes mellitus. More than two-thirds of patients in both groups had a pneumonia severity index score of 3. The pneumonia severity index score is high for this population probably because this measure is strongly influenced by age [12]. Clinical trials involving adults have demonstrated that moxifloxacin is effective against CAP [15 18]. In very elderly patients with CAP (age, 175 years), a pooled analysis of 5 prospective, randomized, controlled trials of intravenous and oral moxifloxacin therapy found similar efficacy and adverse event rates to those observed in the current trial [19]. Comparator agents were clarithromycin and amoxicillin in the oral treatment studies and trovafloxacin, levofloxacin, and amoxicillin/ clavulanate with or without clarithromycin in the intravenous treatment studies [19]. The overall clinical success rates were 93.0% (53 of 57 patients) and 90.2% (83 of 92 patients) for the oral and intravenous moxifloxacin s, respectively (95% CI, 3.2 to 15.9), and 86.4% (38 of 44 patients) and 83.7% (77 of 92 patients) for the oral and intravenous comparator s, respectively (95% CI, 5.4 to 20.9) [19]. Recently, Dunbar et al. [20] reported similar efficacy and safety outcomes between 2 levofloxacin doses (500 mg vs. 750 mg, once daily) for treatment of mild or severe CAP in adult patients. However, the present study is the first comparative evaluation of 2 different fluoroquinolones in hospitalized elderly patients with CAP. The finding that moxifloxacin therapy led to a significantly more rapid clinical improvement and/or Moxifloxacin vs. Levofloxacin for CAP in Elderly Patients CID 2006:42 (1 January) 79

8 resolution of pneumonia than levofloxacin therapy in elderly patients (i.e., between days 3 and 5 after the start of therapy) may be clinically important. This end point should be considered for other CAP clinical trials because it may represent a more sensitive measure of antibiotic efficacy than assessment at the test-of-cure visit. However, it should be noted that, in the current study, there were no differences in duration of stay or duration of intravenous therapy between the 2 regimens. This could, at least in part, be due to the minimum duration of therapy (5 days) mandated by the protocol for patients to be considered for the clinically valid population, and the fact that the total duration of hospitalization in this patient population could have been influenced by other factors, including multiple comorbidities present in these patients. The rate of treatment-emergent adverse events was significantly higher in the moxifloxacin, compared with the levofloxacin. However, the rates of drug-related and serious adverse events were similar for both treatment s. It is possible that the higher rate of adverse events due to any cause was caused by high rates of underlying comorbid illness, including cardiac disease. Moxifloxacin-treated patients experienced fewer drug-related cardiac adverse events than did levofloxacin-treated patients, although this difference was not statistically significant (1.0% vs. 3.5%; P!.2). Diarrhea and oral candidiasis were the 2 most commonly reported drugrelated adverse events in both treatment groups. There was no evidence that moxifloxacin therapy increased the risk of Clostridium difficile diarrhea in elderly patients more than levofloxacin did; there were more occurrences of C. difficile colitis in the levofloxacin (6 patients [3.0%]) than in the moxifloxacin (1 patient [0.5%]), although the difference was not statistically significant ( P p.1). Recent publications suggest that fluoroquinolones may increase the risk of C. difficile colitis [21] and may reduce the effectiveness of subsequent antimicrobial therapy [22]. One study in a long-term care facility showed that gatifloxacin therapy may be associated with a higher rate of C. difficile diarrhea than levofloxacin therapy [21]. Twenty-six patients died during the observation period; most deaths were associated with the severity of comorbid diseases. The mortality rate in this study is lower than those reported elsewhere for hospitalized patients with CAP, which range from 10% to 40% [1, 2, 7, 8]. This difference may be due to the eligibility criteria for this study, which excluded patients who required mechanical ventilation or vasopressors or who had multiorgan failure. An important limitation of this study is that the etiology of CAP could not be identified in the majority of patients. Pneumococcal urine antigen testing and serologic testing for detection of atypical organisms were not performed. Thus, correlation of clinical outcomes with bacteriologic outcomes was not possible for most patients. Also, antimicrobial susceptibility data were not available for all cultured organisms. The organisms isolated most commonly were Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus, as reported by other investigators [2, 8]. In conclusion, sequential intravenous/oral moxifloxacin monotherapy provided significantly higher clinical recovery rates by day 3 5 after initiation of treatment and was as effective, safe, and well tolerated as intravenous/oral levofloxacin monotherapy in hospitalized elderly patients with CAP. Prospective studies are needed to identify the factors associated with duration of antibiotic therapy and hospital stay in this patient population. MEMBERS OF THE STUDY GROUP The Community-Acquired Pneumonia Recovery in the Elderly Study Group included the following investigators: Jack Bernstein, Marvin Bittner, Randy Dotson, Lala Dunbar, Bernard Feinberg, Gary Foley, Michael Habib, Douglas Katula, L. Larsen, Daniel Lee, Arnold Lentnek, Jonathan Maisel, Michael Milam, Henry Covelli, Linda Edwards, Donald Graham, Gary Hunt, Timothy Jackson, Monroe Karetzky, Richard Kohler, Gerry SanPedro, Alvin Teirstein, Richard Wunderink, Clark Gillett, Daniel Lorch, Priscilla Sioson, Ralf Joffe, Mark Metersky, Judy Stone, William Reiter, Derek Knight, James Tan, Kathleen Casey, Steven Knoper, Ata Motamedi, Lillian Oshva, William Salzer, Kim Scholfield, Marcus Zervos, R. Hite, Mark Bochan, Arunabh, R. Stienecker, Michael Natalino, Mazhar Javaid, Steven Berman, John Gezon, Gregory Seymann, Adrian James, Aldona Baltch, Robert Aris, Michael Parry, Charles Andrews, Philip Giordano, William Rodriguez, Peter Vrooman, Jr., Rashmikant Kothari, Colby Grossman, Stuart Simon, Dennis Abella, and W. Boomer. Acknowledgments We thank James Song for performing statistical analysis. Financial support. Bayer Phaceuticals. Manuscript preparation. Statistical analysis was performed by Bayer Phaceuticals. Potential conflicts of interest. A.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.A. was the principal investigator on this study, and the University of Texas Health Science Center at San Antonio was paid for conducting the clinical trial. A.A. has participated as a speaker in scientific meetings or courses organized and financed by various phaceutical companies, including Boehringer Ingelheim, Bayer Pha, Pfizer, GlaxoSmithKline, Wyeth, Sanofi-Aventis, and Altana; has been a consultant for Boehringer Ingelheim, Bayer, Pfizer, GlaxoSmithKline, Wyeth, Sanofi-Aventis, and Altana; and has been the principal investigator for research grants and the University of Texas Heath Science Center at San Antonio and was paid for participating in multicenter clinical trials sponsored by Boehringer Ingelheim, Bayer Pha, BART, Lilly, and the National Institutes of Health. M.S.N. has received honoraria or consulting income from Bayer, Schering Plough, Pfizer, Aventis, Elan, Merck, Wyeth-Ayerst, Chiron, Theravance, and Aerogen. S.H.C. is an employee of Bayer Phaceuticals. All other authors: no conflicts. 80 CID 2006:42 (1 January) Anzueto et al.

9 References 1. Niederman MS, McCombs J, Unger A, Kumar A, Popovian R. The cost of treating community-acquired pneumonia. Clin Ther 1998; 20: Jackson ML, Neuzil KM, Thompson WW, et al. The burden of community-acquired pneumonia in seniors: results of a population-based study. Clin Infect Dis 2004; 39: Kaplan V, Clermont G, Griffin MF, et al. Pneumonia: still the old man s friend? Arch Intern Med 2003; 163: Torres OH, Munoz J, Ruiz D, et al. Outcome predictors of pneumonia in elderly patients: importance of functional assessment. J Am Geriatr Soc 2004; 52: Janssens JP. Pneumonia in the elderly (geriatric) population. Curr Opin Pulm Med 2005; 11: El Solh AA, Brewer T, Okada M, Bashir O, Gough M. Indicators of recurrent hospitalization for pneumonia in the elderly. J Am Geriatr Soc 2004; 52: Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA 1996; 275: Rello J, Rodriguez R, Jubert P, Alvarez B. Severe community-acquired pneumonia in the elderly: epidemiology and prognosis. Study Group for Severe Community-Acquired Pneumonia. Clin Infect Dis 1996; 23: Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 2003; 37: Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163: Morganorth J, DiMarco J, Anzueto A, Niederman MS, Choudhri S. A randomized trial comparing the cardiac rhythm safety of moxifloxacin vs levofloxacin in elderly patients hospitalized with community-acquired pneumonia. The CAPRIE Study Group. Chest 2005; 128: Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify lowrisk patients with community-acquired pneumonia. N Engl J Med 1997; 336: SAS Institute. SAS/STAT user s guide, version 8. Cary, NC: SAS Institute, Song JX, Wassell JT. Sample size for K 2 2 tables in equivalence studies using Cochran s statistic. Control Clin Trials 2003; 24: Fogarty C, Grossman C, Williams J, Haverstock D, Church D. Efficacy and safety of moxifloxacin vs clarithromycin for community-acquired pneumonia. Infect Med 1999; 16: File TM, Larsen SL, Fogarty CM, et al. Safety and efficacy of sequential (iv to po) moxifloxacin for the treatment of community-acquired pneumonia in hospitalized patients. Today s Ther Trends 2001; 19: Welte T, Petermann W, Schuermann D, Bauer TT, Reimnitz P. Treatment with sequential intravenous or oral moxifloxacin was associated with faster clinical improvement than was standard therapy in hospitalized patients with community-acquired pneumonia who received initial parenteral therapy. The MOXIRAPID Study Group. Clin Infect Dis 2005: 41: Finch R, Schurmann D, Collins O, et al. Randomized controlled trial of sequential intravenous (iv) and oral moxifloxacin compared with sequential iv and oral co-amoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral treatment. Antimicrob Agents Chemother 2002; 46: Choudhri SH, Haverstock D, Kruesmann F. Efficacy of po and iv moxifloxacin in the treatment of community-acquired pneumonia (CAP) in the very elderly (age 175 years) [abstract 172]. In: Program and abstracts of the 40th Annual Meeting of the Infectious Diseases Society of America (Chicago, IL). Alexandria, VA: Infectious Diseases Society of America, 2002: Dunbar LM, Wunderink RG, Habib MP, et al. High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis 2003; 37: Gaynes R, Rimland D, Killum E, et al. Outbreak of Clostridium difficile infection in a long-term care facility: association with gatifloxacin use. Clin Infect Dis 2004; 38: Ackermann G, Tang-Feldman YJ, Schaumann R, et al. Antecedent use of fluoroquinolones is associated with resistance to moxifloxacin in Clostridium difficile. Clin Microbiol Infect 2003; 9: Moxifloxacin vs. Levofloxacin for CAP in Elderly Patients CID 2006:42 (1 January) 81

10 ERRATA In an article published in the 1 January 2006 issue of the journal (Anzueto A, Niederman MS, Pearle J, Restrepo MI, Heyder A, Choudhri SH. Community-aquired pneumonia recovery in the elderly (CAPRIE): efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy. Community-Acquired Pneumonia Recovery in the Elderly Study Group. Clin Infect Dis 2006; 42:73 81), an error appeared in footnote b in table 2. The footnote should read Six strains were fluoroquinolone susceptible, and 1 strain from a patient in the levofloxacin was intermediate (levofloxacin MIC, 4 mg/l) (not Six strains were fluoroquinolone susceptible, and 1 strain from a patient in the levofloxacin was intermediate (moxifloxacin MIC, 4 mg/l). ) The authors regret this error. In an article published in the 15 May 2002 issue of the journal (Mylonakis E, Kallas WM, Fishman JA. Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients. Clin Infect Dis 2002; 34: ), an error appeared in the third sentence of the third paragraph of the Discussion section. The corrected sentence should read as follows: The functional consequence of the UL97 mutations is impaired phosphorylation of ganciclovir in virus-infected not cells, with the consequent lack of synthesis of ganciclovir triphosphate, the active form of the drug [4, p. 286]. The functional consequence of the UL97 mutations is impaired phosphorylation of ganciclovir in virus-infected cells, with the consequent lack of synthesis of ganciclovir triphosphate, the active form of the drug [4]. The authors regret this error. Clinical Infectious Diseases 2006; 42: by the Infectious Diseases Society of America. All rights reserved /2006/ $ CID 2006:42 (1 May) ERRATA