MAJOR ARTICLE

Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE): Efcacy and Safety of Moxioxacin Therapy versus That of Levooxacin 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 Groupa
1

Department of Medicine, University of Texas Health Science Center, and 2Veterans Evidence Based Research Dissemination and Implementation Center, Department of Medicine, South Texas Veterans Healthcare System, San Antonio, Texas; 3Department of Medicine, Winthrop-University Hospital, Mineola, New York; 4California Research Medical Group, Fullerton, California; 5Carolina Research Specialists, Elizabeth City, North Carolina; and 6Bayer Pharmaceuticals, West Haven, Connecticut

Background. Limited prospective data are available for elderly patients with community-acquired pneumonia (CAP). This study aimed to determine the efcacy and safety of moxioxacin versus that of levooxacin 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 stratied by CAP severity before randomization to receive treatment with either intravenous/oral moxioxacin (400 mg daily) or intravenous/oral levooxacin (500 mg daily) for 714 days. Clinical response at test-of-cure (the primary efcacy 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 moxioxacin group and 199 in the levooxacin group). The population eligible for clinical efcacy analysis (i.e., the clinically valid population) included 281 patients (141 in the moxioxacin group and 140 in the levooxacin group); 51.3% were male, and the mean age ( SD) was 77.4 7.7 years. Cure rates at test-of-cure for the clinically valid population were 92.9% in the moxioxacin arm and 87.9% in the levooxacin arm (95% condence interval [CI], 1.9 to 11.9; P p .2). Clinical recovery by days 35 after the start of treatment was 97.9% in the moxioxacin arm vs. 90.0% in the levooxacin arm (95% CI, 1.714.1; P p .01). In the moxioxacin 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 levooxacin group (P p not signicant). Cure rates in the moxioxacin arm were 90.0% for patients aged 6574 years and 94.5% for patients aged 75 years, compared with 85.0% and 90.0%, respectively, in the levooxacin arm (P p not signicant). There were no statistically signicant differences between the treatment groups with regard to drug-related adverse events. Conclusions. Intravenous/oral moxioxacin therapy was efcacious 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 levooxacin therapy, with a comparable safety prole. In the United States, community-acquired pneumonia (CAP) accounts for 15.6 million cases and 1 million hospitalizations annually [1]. A retrospective cohort 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 6569 years, 27.9 cases/1000 person-years for those aged 7579 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

Received 1 July 2005; accepted 23 August 2005; electronically published 22 November 2005. Presented in part: International Conference of the American Thoracic Society, San Diego, CA, 2025 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 78229 (Anzueto@uthscsa.edu). Clinical Infectious Diseases 2006; 42:7381 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4201-0012$15.00

Moxioxacin vs. Levooxacin for CAP in Elderly Patients CID 2006:42 (1 January) 73

within 18 months [4]. Accordingly, institution of appropriate antibiotic therapy is imperative for elderly patients, to prevent unnecessary morbidity and death [3, 58]. Updated CAP treatment guidelines recommend uoroquinolone 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 uoroquinolones in hospitalized elderly patients with CAP. Thus, the primary purpose of this study was to compare the efcacy of sequential intravenous/oral moxioxacin therapy with levooxacin 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 institutions internal review board approved the study protocol; written informed consent was obtained from each patient. After stratication by disease severity with the revised American Thoracic Society criteria (mild/moderate vs. severe) [10], patients were randomly assigned to receive either intravenous moxioxacin, 400 mg once daily, or intravenous levooxacin, 500 mg once daily, for 714 days. Patients were also assigned a Pneumonia Outcome Research Team pneumonia severity index score [12], although it was not used for stratication. For patients with a documented and/or a calculated creatinine clearance rate of 2049 mL/min, the intravenous dose of levooxacin therapy was a 500-mg loading dose, followed by a dosage of 250 mg once daily for 714 days. Treatment with moxioxacin did not require dosage adjustment for these patients. Patients could be switched to oral therapy at the investigators discretion (moxioxacin, 400 mg once daily, or levooxacin, 250500 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, uids, 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 conrmed evidence of a new and/or progressive inltrate(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 eld) or a change in sputum character (increased volume and/or purulence), dyspnea and/or tachypnea (respiratory rate of 120
74 CID 2006:42 (1 January) Anzueto et al.

breaths/min), rigors and/or chills, pleuritic chest pain, auscultatory ndings 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/mm3 or 15% immature neutrophils (bands; regardless of peripheral WBC count) or leukopenia (total WBC count of !4500 cells/mm3). 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 debrillator, 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 nonuoroquinolone 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/mm3), severe hepatic insufciency (Child-Pugh classication 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 rst 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 eld and 25 leukocytes per low-power eld. 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 denitions. Clinical response at the test-of-cure visit (between days 5 and 21 after the end of therapy) was the primary efcacy outcome. Secondary efcacy 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 efcacy

Figure 1. Patient ow in a clinical trial of the efcacy and safety of moxioxacin versus that of levooxacin 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 efcacy analysis. Clinical response at the test-of-cure visit was dened as cure (disappearance of acute signs and symptoms related to the infection or sufcient improvement such that additional or alternative antimicrobial therapy was not required), failure (failure to respond or insufcient 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 dened 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. Bac-

teriologic responses during therapy and at the test-of-cure visit were dened 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 dened 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 denitely, probably, or possibly related to the study drug. Serious adverse reactions were dened 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 nal dose of study drug. Serial blood and urine samples were collected throughout the study for routine hematologic, chemistry, and coagulation evaluations and for urinalysis.

Moxioxacin vs. Levooxacin for CAP in Elderly Patients CID 2006:42 (1 January) 75

Table 1. Baseline demographic and medical characteristics of the clinically valid population in a clinical trial of the efcacy and safety of moxioxacin versus levooxacin for the treatment of hospitalized elderly patients with community-acquired pneumonia (CAP).
Moxioxacin arm (n p 141) 69 (48.9) 118 (83.7) 12 (8.5) 11 (7.8) 77.9 7.1 6595 91 (64.5) 68 (48.2) 41 (29.1) 10 (7.1) 19 (13.5) 6 (4.3) 48 Levooxacin arm (n p 140) 71 (50.7) 123 (87.9) 7 (5.0) 9 (6.4) 1 (0.7) 77.4 7.7 6598 80 (57.1) 57 (40.7) 51 (36.4) 6 (4.3) 26 (18.6) 7 (5.0) 57 .6 .2 .2

Characteristic Male sex Race White Black Hispanic Asian Age, years Mean SD Range
175 Pneumonia severity index score 13 4 5 Severe ATS CAP severity scorea

P .8 .5

Nursing home residence Smoking history, mean pack-years Comorbidity Cardiac disorder Any Coronary artery disease Congestive heart failure Ischemic disorder Respiratory disorder Any Bronchospasm and obstruction Parenchymal lung disorders Conditions associated with abnormal gas exchange Diabetes mellitus Estimated creatinine clearance rate !50 mL/min
a

.2 .7 .1

102 54 45 27

(72.3) (38.3) (31.9) (19.1)

107 48 51 27

(76.4) (34.3) (36.4) (19.3)

.5 .6 .5 1.0 .06 .3 .8 .6 .9 .4

97 (68.9) 87 (61.7) 25 (17.7) 7 (5.0) 40 (28.4) 69 (48.9)

111 (79.3) 96 (68.6) 22 (15.7) 10 (7.1) 38 (27.1) 61 (43.6)

NOTE. Data are no. (%) of patients, unless otherwise indicated. 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 efcacy objective was to show that moxioxacin therapy was not inferior to levooxacin 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-MantelHaenszel method was used to calculate 95% CIs [14]. Secondary efcacy 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 efcacy outcome variable (i.e.,

76 CID 2006:42 (1 January) Anzueto et al.

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, 1.714.1 (P p .01 ). B, Clinical cure at the test-of-cure visit (i.e., primary efcacy 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 x2 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 (gure 1). The clinically valid population included 141 patients in the moxioxacin group and 140 patients in the levooxacin 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 77.9 7.1 years, with

Figure 3. Clinical cure rates at the test-of-cure visit for the clinically valid population, stratied by community-acquired pneumonia (CAP) severity (A) and age (B).

Moxioxacin vs. Levooxacin for CAP in Elderly Patients CID 2006:42 (1 January) 77

Table 2. Baseline positive culture results for and most common pathogens isolated from elderly patients who received moxioxacin or levooxacin for the treatment of community-acquired pneumonia (CAP).
No. (%) of patients Moxioxacin arm a (n p 21) 17 (81.0) 5 (23.8) 7 (33.3) 3 (14.3) 3 (14.3) 2 (9.5) Levooxacin arm (n p 30) 22 (73.3) 8 (26.7) 10 (33.3) 9 (30) 7 (23.3) 5 (16.7)

Variable Positive culture result, by culture site Respiratory Blood Pathogen isolated Streptococcus pneumoniae Haemophilus inuenzae Staphylococcus aureus Pseudomonas aeruginosab

NOTE. All patients had negative results of urinary antigen tests for detection of Legionella pneumophila. One patient had an organism isolated from cultures of respiratory and blood specimens. b Six strains were uoroquinolone susceptible, and 1 strain from a patient in the levooxacin arm was intermediate (moxioxacin MIC, 4 mg/L).
a

60.9% of patients aged 75 years. Patients in this population had a mean number of 18.8 comorbidities (18.3 in the moxioxacin group and 19.3 in the levooxacin 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 10.0 2.7 days for the moxioxacin arm and 10.0 2.9 days for the levooxacin arm (P 1 .8). The mean duration ( SD) of intravenous therapy was 3.7 2.0 days for the moxioxacin arm versus 3.8 2.2 days for levooxacin arm (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 moxioxacin arm vs. 88.6% in the levooxacin arm; P p .2). Clinical outcomes. At the test-of-cure visit, the clinical cure rate (i.e., the primary efcacy outcome) for the clinically valid population was 92.9% for the moxioxacin arm and 87.9% for the levooxacin arm (95% CI, 1.9 to 11.9; P p .2) (gure 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 moxioxacin arm, compared with 90.0% of patients in the levooxacin arm, had achieved clinical recovery (95% CI, 1.714.1; P p .01) (gure 2). Univariate analysis identied the following risk factors as inuences of clinical outcome (gure 3): for severe CAP, the rates of clinical cure were 94.7% in the moxioxacin arm and 84.6% in the levooxacin arm (95% CI, 0.12 to 0.32; P p .5); for patient age, the clinical cure rates for those aged 65 74 years were 90.0% in the moxioxacin arm and 85.0% in the levooxacin arm (95% CI, 0.09 to 0.19; P p .6), and the rates for those aged 75 years were 94.5% and 90.0%, re78 CID 2006:42 (1 January) Anzueto et al.

spectively (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 moxioxacin arm vs. 50.0% [8 of 16 patients] in the levooxacin arm). Multiple regression analysis using various combinations of risk factors failed to show a statistically signicant 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 moxioxacin arm and 30 [58.8%] in the levooxacin arm) had 59 baseline pathogens identied 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 moxioxacin arm (17 of 21 patients) and 75.0% in the levooxacin arm (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 moxioxacin arm (17 of 21 patients) versus 76.7% in the levooxacin arm (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 signicantly higher in the moxioxacin-treated patients (P p .01 ) (table 3), although the rates of drug-related and serious adverse events were similar for both treatment arms. 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 moxioxacin arm and 7 in the levooxacin arm). Serious adverse events were reported for 23% of patients in both treatment groups (P p .9). No clinically signicant 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 nal dose of study drug. Only 6 moxioxacin- and 3 levooxacin-treated patients died during therapy or within the rst 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 patients comorbid diseases. Health resource utilization. For the clinically valid population, the total duration of hospital stay ( SD) was 7.5 4.2 days in the moxioxacin arm and 7.5 4.6 days in the levooxacin arm (P p .95), with a mean duration ( SD) of 6.8 4.1 days and 6.8 4.6 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.

Table 3. Overview of adverse events for hospitalized elderly patients eligible who received moxioxacin or levooxacin for the treatment of community-acquired pneumonia.
No. (%) of patients Moxioxacin arm (n p 195) 164 (84.1) 15 (7.7) 46 (23.6) 15 (7.7) 51 (26.2) Levooxacin arm (n p 199) 146 (73.4) 20 (10.1) 45 (22.6) 11 (5.5) 45 (22.6)

Variable Treatment-emergent adverse event Discontinued treatment due to adverse event Serious adverse event Death Any drug-related adverse event Drug-related adverse event reported by 11.5% of patients in either treatment group Diarrhea Oral candidiasis Nausea Clostridium difcile infection/colitis Cardiac event Atrial brillation Ventricular tachycardia Acute myocardial infarction Atrial utter Congestive heart failure Cardiorespiratory arrest Supraventricular tachycardia Torsade de pointes Chest pain Increased heart rate

P .01 .5 .9 .5 .5

11 (5.6) 7 (3.6) 3 (1.5) 1 2 0 1 0 0 0 0 1 0 0 0 (0.5) (1.0) (0.5)

10 (5.0) 7 (3.5) 4 (2.0) 6 7 3 1 1 1 1 1 0 1 1 1 (3.0) (3.5) (1.5) (0.5) (0.5) (0.5) (0.5) (0.5) (0.5) (0.5) (0.5)

1.0 1.0 1.0 .1 .2

(0.5)

DISCUSSION In this prospective, randomized, double-blind trial involving hospitalized elderly patients with CAP, moxioxacin-treated patients were more likely to have clinical improvement by treatment day 35 than were levooxacin-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 moxioxacin group, although the incidence of drug-related adverse events was similar to that in the levooxacin group. In subgroup analyses based on CAP severity and patient age, clinical cure rates in the moxioxacin arm were consistently higher than, although not statistically signicantly different from, those for levooxacin. This trial included 394 elderly patients with a mean age ( SD) of 77.4 7.7 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 inuenced by age [12].

Clinical trials involving adults have demonstrated that moxioxacin is effective against CAP [1518]. In very elderly patients with CAP (age, 175 years), a pooled analysis of 5 prospective, randomized, controlled trials of intravenous and oral moxioxacin therapy found similar efcacy and adverse event rates to those observed in the current trial [19]. Comparator agents were clarithromycin and amoxicillin in the oral treatment studies and trovaoxacin, levooxacin, 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 moxioxacin arms, 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 arms, respectively (95% CI, 5.4 to 20.9) [19]. Recently, Dunbar et al. [20] reported similar efcacy and safety outcomes between 2 levooxacin doses (500 mg vs. 750 mg, once daily) for treatment of mild or severe CAP in adult patients. However, the present study is the rst comparative evaluation of 2 different uoroquinolones in hospitalized elderly patients with CAP. The nding that moxioxacin therapy led to a signicantly more rapid clinical improvement and/or

Moxioxacin vs. Levooxacin for CAP in Elderly Patients CID 2006:42 (1 January) 79

resolution of pneumonia than levooxacin 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 efcacy 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 inuenced by other factors, including multiple comorbidities present in these patients. The rate of treatment-emergent adverse events was signicantly higher in the moxioxacin arm, compared with the levooxacin arm. However, the rates of drug-related and serious adverse events were similar for both treatment arms. 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. Moxioxacin-treated patients experienced fewer drug-related cardiac adverse events than did levooxacin-treated patients, although this difference was not statistically signicant (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 moxioxacin therapy increased the risk of Clostridium difcile diarrhea in elderly patients more than levooxacin did; there were more occurrences of C. difcile colitis in the levooxacin arm (6 patients [3.0%]) than in the moxioxacin arm (1 patient [0.5%]), although the difference was not statistically signicant (P p .1 ). Recent publications suggest that uoroquinolones may increase the risk of C. difcile colitis [21] and may reduce the effectiveness of subsequent antimicrobial therapy [22]. One study in a long-term care facility showed that gatioxacin therapy may be associated with a higher rate of C. difcile diarrhea than levooxacin 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 identied 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
80 CID 2006:42 (1 January) Anzueto et al.

possible for most patients. Also, antimicrobial susceptibility data were not available for all cultured organisms. The organisms isolated most commonly were Streptococcus pneumoniae, Haemophilus inuenzae, and Staphylococcus aureus, as reported by other investigators [2, 8]. In conclusion, sequential intravenous/oral moxioxacin monotherapy provided signicantly higher clinical recovery rates by day 35 after initiation of treatment and was as effective, safe, and well tolerated as intravenous/oral levooxacin 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 Scholeld, 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 Pharmaceuticals. Manuscript preparation. Statistical analysis was performed by Bayer Pharmaceuticals. Potential conicts of interest. A.A. does not have a nancial 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 scientic meetings or courses organized and nanced by various pharmaceutical companies, including Boehringer Ingelheim, Bayer Pharma, Pzer, GlaxoSmithKline, Wyeth, Sano-Aventis, and Altana; has been a consultant for Boehringer Ingelheim, Bayer, Pzer, GlaxoSmithKline, Wyeth, Sano-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 Pharma, BART, Lilly, and the National Institutes of Health. M.S.N. has received honoraria or consulting income from Bayer, Schering Plough, Pzer, Aventis, Elan, Merck, Wyeth-Ayerst, Chiron, Theravance, and Aerogen. S.H.C. is an employee of Bayer Pharmaceuticals. All other authors: no conicts.

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Moxioxacin vs. Levooxacin for CAP in Elderly Patients CID 2006:42 (1 January) 81

E R R ATA

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): efcacy and safety of moxioxacin therapy versus that of levooxacin therapy. Community-Acquired Pneumonia Recovery in the Elderly Study Group. Clin Infect Dis 2006; 42:7381), an error appeared in

footnote b in table 2. The footnote should read Six strains were uoroquinolone susceptible, and 1 strain from a patient in the levooxacin arm was intermediate (levooxacin MIC, 4 mg/L) (not Six strains were uoroquinolone susceptible, and 1 strain from a patient in the levooxacin arm was intermediate (moxioxacin 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; 34:1337 41), 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

cells, with the consequent lack of synthesis of ganciclovir triphosphate, the active form of the drug [4, p. 286]. not 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; 42:1350 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4209-0027$15.00

1350 CID 2006:42 (1 May) ERRATA