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 Groupa

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 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 77.4 7.7 years. Cure rates at test-of-cure for the clinically valid population were 92.9% in the moxifloxacin arm and 87.9% in the levofloxacin arm (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 arm vs. 90.0% in the levofloxacin arm (95% CI, 1.7–14.1; 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 arm were 90.0% for patients aged 65–74 years and 94.5% for patients aged 75 years, compared with 85.0% and 90.0%, respectively, in the levofloxacin arm (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 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 65–69 years, 27.9 cases/1000 person-years for those aged 75–79 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, 20–25 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 ( Clinical Infectious Diseases 2006; 42:73–81 2005 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4201-0012$15.00

Moxifloxacin vs. Levofloxacin for CAP in Elderly Patients • CID 2006:42 (1 January) • 73

4 F]. Treatment with moxifloxacin did not require dosage adjustment for these patients. Clinical and bacteriologic evaluations. For patients with a documented and/or a calculated creatinine clearance rate of 20–49 mL/min. a requirement for initial parenteral therapy. 400 mg once daily. 500 mg once daily. or a tympanic temperature of 38. to prevent unnecessary morbidity and death [3. Updated CAP treatment guidelines recommend fluoroquinolone monotherapy or b-lactam plus macrolide combination therapy for hospitalized patients with CAP [9. 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. The trial population included hospitalized elderly patients (age. 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.e. Patients were considered to be eligible for the clinical efficacy . 400 mg once daily.within 18 months [4]. mechanical endobronchial obstruction. A separate publication involving this same patient population and protocol describes the primary safety variable (i.2 F]) or hypothermia (rectal or core temperature of !35 C [95. However. Clinical and bacteriologic outcome definitions. institution of appropriate antibiotic therapy is imperative for elderly patients. previous history of tendinopathy with quinolones. or known hypersensitivity to study medications. Patients could be switched to oral therapy at the investigator’s discretion (moxifloxacin. auscultatory findings of rales and/or crackles on pulmonary examination and/or evidence of pulmonary consolidation. Additional sputum specimens were obtained from patients with clinical failure. 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. dyspnea and/or tachypnea (respiratory rate of 120 74 • CID 2006:42 (1 January) • Anzueto et al. need for mechanical ventilation. a rectal temperature of 39 C [102. during treatment (between days 3 and 5 after the start of treatment). significant bradycardia (heart rate of !50 beats/min).2 F]). severe hepatic insufficiency (Child-Pugh classification of C). pleuritic chest pain. known prolongation of the corrected QT interval or use of class IA or class III antiarrhythmics. and each institution’s internal review board approved the study protocol.. 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). regardless of peripheral WBC count) or leukopenia (total WBC count of !4500 cells/mm3). for 7–14 days. Thus. fluids. written informed consent was obtained from each patient. 10]. 250–500 mg once daily) after 2 days of intravenous therapy if they demonstrated improvement during intravenous therapy. double-blind. known HIV infection (CD4 cell count of !200 cells/mm3). randomized controlled. no prospective clinical trials have been published that compare fluoroquinolones in hospitalized elderly patients with CAP. A prospective. and if results of culture were positive. Cultures were performed if Gram staining revealed 10 squamous epithelial cells per low-power field and 25 leukocytes per low-power field. rigors and/or chills. Patients were also assigned a Pneumonia Outcome Research Team pneumonia severity index score [12]. 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. systemic antibacterial therapy for 124 h within 7 days of enrollment unless therapy failed after receiving 172 h of a nonfluoroquinolone antibiotic. fever (an oral temperature of 38 C [100.5 C [101. and a WBC count of 10. uncorrected hypokalemia. the intravenous dose of levofloxacin therapy was a 500-mg loading dose. severe) [10]. Clinical signs and symptoms were evaluated before treatment (within 48 h before receipt of the first dose of study drug). implanted cardiac defibrillator. Accordingly. PATIENTS AND METHODS Study design and treatment. 65 years) with clinical signs and symptoms of CAP. Patient population. Blood specimens were obtained at enrollment. Patients with any of the following characteristics were excluded from the study: hospitalization for 148 h before pneumonia development. although it was not used for stratification. and could tolerate oral food. samples were obtained and cultured every 48 h until results were negative. and medications without vomiting or diarrhea. renal impairment (serum creatinine clearance rate of !20 mL/min). chronic therapy (duration of 2 weeks) with immunosuppressant therapy (115 mg/day of systemic prednisone or equivalent). known or suspected active tuberculosis or endemic fungal infection. neutropenia (neutrophil count of !1000 neutrophils/mL). A urinary antigen test for detection of Legionella pneumophila was performed. The study was conducted in accordance with the Declaration of Helsinki. breaths/min). Both oral medications were encapsulated for blinding. patients were randomly assigned to receive either intravenous moxifloxacin. After stratification by disease severity with the revised American Thoracic Society criteria (mild/moderate vs. Clinical response at the test-of-cure visit (between days 5 and 21 after the end of therapy) was the primary efficacy outcome. or intravenous levofloxacin. double-dummy. comparative study was conducted from November 2002 to April 2004 at 47 study centers in the United States. followed by a dosage of 250 mg once daily for 7–14 days. radiologically confirmed evidence of a new and/or progressive infiltrate(s). or levofloxacin. cardiac adverse events) [11].000 cells/mm3 or 15% immature neutrophils (bands. 5–8].2 F]. were afebrile for 8 h.

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

4 7. on the basis of clinical response at the test-of-cure visit for the clinically valid population.5) 6 (4.5 . (%) of patients.2 .2 Characteristic Male sex Race White Black Hispanic Asian Age.8 .6 .8 .1) 19 (13.9 . All statistical analyses were performed using SAS (SAS Institute) [13].6) NOTE.3) (38. Statistical analysis.7) 51 (36.0) 57 .1) 10 (7.4) (34.9) (19.6) 22 (15.7) 77. Moxifloxacin arm (n p 141) 69 (48. Logistic regression was performed to evaluate treatment effect on the primary dependent efficacy outcome variable (i.3) .7) 12 (8.9) 87 (61. giving a power of 76% by using a D (critical difference) of 10% or a power of 90% by using a D of 15%. 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 .5 Nursing home residence Smoking history. According to 2001 guidelines of the American Thoracic Society (ATS) [10]. as well as bacteriologic outcomes.06 .6) 7 (5.5) 11 (7. Data on the total duration of hospital stay.6 . years Mean SD Range 175 Pneumonia severity index score 1–3 4 5 Severe ATS CAP severity scorea P .9 7. The primary efficacy objective was to show that moxifloxacin therapy was not inferior to levofloxacin therapy for the treatment of CAP.0 .1 65–95 91 (64.3) 48 Levofloxacin arm (n p 140) 71 (50.9) 7 (5.1) 57 (40.6 . The Cochran-MantelHaenszel method was used to calculate 95% CIs [14].1) 61 (43.0) 40 (28.0) 9 (6..1) 107 48 51 27 (76. 76 • CID 2006:42 (1 January) • Anzueto et al.3) 26 (18.3) 96 (68. Secondary efficacy end points included clinical outcome at other time points in the intention-to-treat and microbiologically valid populations. Data are no. Health resource utilization assessment. total duration of antimicrobial therapy.8) … 77. .3) (31.9) 118 (83.4 97 (68.3 .7) 7 (5.4) 6 (4.5) 68 (48.1) 38 (27.7) 10 (7. unless otherwise indicated.2) 41 (29.9) 111 (79. 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).1 102 54 45 27 (72.e.3) (36.4) 69 (48. 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. duration of intensive care unit (ICU) stay. and duration of intravenous therapy were collected at the test-of-cure visit.4) 1 (0.7) 123 (87.7 .7) 25 (17.5 1.7 65–98 80 (57.Table 1.4) (19.2 .

race.9 7. Levofloxacin for CAP in Elderly Patients • CID 2006:42 (1 January) • 77 .20.9 (P p . age. the safety population included 394 patients (figure 1). adverse events. B. body mass index. Continuous independent variables were treated as continuous. Demographic and clinical characteristics at baseline. The clinically valid population had a mean age ( SD) of 77. Moxifloxacin vs.7–14. 7 received no study medication. aspiration pneumonia.e. Multiple logistic regression was performed with only those variables with P values of !. and laboratory data were summarized using descriptive statistics. smoking history. presence of pathogen at baseline. †95% CI for difference. pretreatment hospitalization history. and treatment groups were compared using 1-way analysis of variance for continuous variables or x2 analysis for categorical data. primary residence. with Figure 3. Thus. and health status. Baseline demographic and clinical characteristics for the clinically valid population are summarized in table 1 and were similar between the 2 treatment groups.1 years. pneumonia severity index score. infection duration. sequence of intravenous dosing.01 ). Clinical recovery during therapy (between days 3 and 5 after the start of treatment). clinical response at the test-of-cure visit) after adjusting for risk factors. RESULTS Patient disposition and demographic characteristics.9 to 11.. switch from intravenous to oral treatment.1 (P p . stratified by community-acquired pneumonia (CAP) severity (A) and age (B). Clinical outcomes for the clinically valid population: A. 1.Figure 2. Clinical cure rates at the test-of-cure visit for the clinically valid population. Treatment effect was evaluated after adjusting for other confounding factors in the regression model from the univariate analyses. Of 401 patients randomly assigned to receive study therapy.2). The clinically valid population included 141 patients in the moxifloxacin group and 140 patients in the levofloxacin group. *95% CI for difference. Clinical cure at the test-of-cure visit (i. 1. including sex. with no collapsing done for the analysis. primary efficacy outcome).

97.8 4..3) 3 (14.6% in the levofloxacin arm (95% CI.and 3 levofloxacin-treated patients died during therapy or within the first 7 days after therapy.7).0% in the levofloxacin arm (95% CI. At the test-of-cure visit.14.7–14. At the during treatment visit (between days 3 and 5 after the start of therapy) for the clinically valid population.0% in the moxifloxacin arm and 85. 0. 0.3) 9 (30) 7 (23. Patients in this population had a mean number of 18. 51 (18.6 days.01 ) (table 3). There were no differences in health resource utilization between patients with positive versus those with negative results of pretherapy bacterial cultures.2). No clinically significant differences between treatment groups were seen for clinical laboratory test values or vital signs.8 2.5) Levofloxacin arm (n p 30) 22 (73. 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).7) Variable Positive culture result.0% in the moxifloxacin arm (17 of 21 patients) versus 76.0% in the levofloxacin arm (21 of 28 patients) (P p . Bacteriologic success (i. No.9 to 11.8) 7 (33. b Six strains were fluoroquinolone susceptible.6 days in the levofloxacin arm (P p .7 days for the moxifloxacin arm and 10. for patient age. 0.0% of patients in the levofloxacin arm.9 days for the levofloxacin arm (P 1 .9% of patients aged 75 years. for hospital stay after the initiation of study drug treatment (P p . P p . respectively.7% in the levofloxacin arm (23 of 30 patients) (95% CI. by culture site Respiratory Blood Pathogen isolated Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Pseudomonas aeruginosab NOTE.2%] in the moxifloxacin arm and 30 [58.2 days in the moxifloxacin arm and 7.1%) of 281 (21 [41.0 2. and all were determined by the investigators to be due to the patient’s comorbid diseases. Safety and tolerability.1.31. There was no difference in mortality between the 2 treatment groups (P p . and the majority of deaths occurred 17 days after receipt of the final dose of study drug.19. 50. 88.1 days and 6. Only 6 moxifloxacin.9.3) 3 (14.0. P p . 17 (48. the total duration of hospital stay ( SD) was 7. The rate of treatment-emergent adverse events due to any cause was significantly higher in the moxifloxacin-treated patients (P p . the total duration of hospital stay was similar between the treatment groups.22 to 0. re78 • CID 2006:42 (1 January) • Anzueto et al.0 2.e.5% and 90. P p .9% for the levofloxacin arm (95% CI.6% in the moxifloxacin arm vs. There was no difference between treatments with regard to the rate of premature discontinuation owing to an adverse event.9). (%) of patients Moxifloxacin arm a (n p 21) 17 (81.0% in the moxifloxacin arm (17 of 21 patients) and 75. although the rates of drug-related and serious adverse events were similar for both treatment arms.7% in the moxifloxacin arm and 84.8 comorbidities (18. Multiple regression analysis using various combinations of risk factors failed to show a statistically significant higher cure rate between treatment groups. For patients in the ICU.09 to 0.67).32. P p .9% of patients in the moxifloxacin arm.e. and the rates for those aged 75 years were 94.8 4. the clinical cure rate (i.5 4. spectively (95% CI.2 days for levofloxacin arm (P p . the mean duration ( SD) of total antimicrobial therapy was 10.01) (figure 2).8%] in the levofloxacin arm) had 59 baseline pathogens identified in sputum or blood specimens and constituted the microbiologically valid population (table 2).3) 5 (16. Clinical outcomes.3) 2 (9. and the mean number of pretreatment medications was 6. 0. the clinical cure rates for those aged 65– 74 years were 90.98).05 to 0. 1. 1.0%.. For the clinically valid population. a ∼60.3 in the levofloxacin group.9% for the moxifloxacin arm and 87.Table 2. Serious adverse events were reported for ∼23% of patients in both treatment groups (P p . Univariate analysis identified the following risk factors as influences of clinical outcome (figure 3): for severe CAP.3 in the moxifloxacin group and 19. P p .6% [5 of 9 patients] in the moxifloxacin arm vs.0) 5 (23.3) 8 (26.9 ). and 1 strain from a patient in the levofloxacin arm was intermediate (moxifloxacin MIC.5). For the clinically valid population.0 days for the moxifloxacin arm versus 3.5 4.4). None of the deaths were considered to be drug related.7 2. the rates of clinical cure were 94. with a mean duration ( SD) of 6.6%) of 35 of these events were considered to be drug related (10 in the moxifloxacin arm and 7 in the levofloxacin arm). eradication or presumed eradication of the causal pathogen) at the test-of-cure visit was 81. Bacteriologic outcomes. The majority of patients were switched to oral therapy on day 3 or 4 after the start of therapy (93.95).5).0% [8 of 16 patients] in the levofloxacin arm). and patients who were still receiving intravenous therapy at the test-of-cure visit had lower clinical cure rates (55. All patients had negative results of urinary antigen tests for detection of Legionella pneumophila. P p . P p .6). had achieved clinical recovery (95% CI.7) 10 (33. .12 to 0.6% in the levofloxacin arm.8). P p . The bacteriologic response was in agreement with the clinical response: clinical cure rates for the microbiologically valid population were 81. Health resource utilization.95 ). 4 mg/L). One patient had an organism isolated from cultures of respiratory and blood specimens. The mean duration ( SD) of intravenous therapy was 3. the primary efficacy outcome) for the clinically valid population was 92. compared with 90.2) (figure 2). Of the patients in the clinically valid population.

This trial included 394 elderly patients with a mean age ( SD) of 77.5 . controlled trials of intravenous and oral moxifloxacin therapy found similar efficacy and adverse event rates to those observed in the current trial [19]. There was a higher incidence of adverse events due to any cause in the moxifloxacin group.0) 7 (3. In subgroup analyses based on CAP severity and patient age. 5. double-blind trial involving hospitalized elderly patients with CAP.4% (38 of 44 patients) and 83. The overall clinical cure rate and bacteriologic success rates were similar between the 2 treatment groups.9 . 60. The finding that moxifloxacin therapy led to a significantly more rapid clinical improvement and/or Moxifloxacin vs.5) (0. although not statistically significantly different from. Most patients had concomitant comorbid conditions.6) 11 (5. Comparator agents were clarithromycin and amoxicillin in the oral treatment studies and trovafloxacin. once daily) for treatment of mild or severe CAP in adult patients.0) (0. 750 mg. Levofloxacin for CAP in Elderly Patients • CID 2006:42 (1 January) • 79 .5% of patients in either treatment group Diarrhea Oral candidiasis Nausea Clostridium difficile infection/colitis Cardiac event Atrial fibrillation Ventricular tachycardia Acute myocardial infarction Atrial flutter Congestive heart failure Cardiorespiratory arrest Supraventricular tachycardia Torsade de pointes Chest pain Increased heart rate P .0) (3. The pneumonia severity index score is high for this population probably because this measure is strongly influenced by age [12]. randomized. Dunbar et al. No. In very elderly patients with CAP (age. (%) of patients Moxifloxacin arm (n p 195) 164 (84. moxifloxacin-treated patients were more likely to have clinical improvement by treatment day 3–5 than were levofloxacin-treated patients.5) (1. a pooled analysis of 5 prospective. including cardiac.5) 1.5) 10 (5.5) (0. [20] reported similar efficacy and safety outcomes between 2 levofloxacin doses (500 mg vs.5) 45 (22.5) (0.5) (0.7) 46 (23.0 . gastrointestinal. randomized.5 .2) Levofloxacin arm (n p 199) 146 (73.4) 20 (10.7) 51 (26. 3. More than two-thirds of patients in both groups had a pneumonia severity index score of 3.01 .5) (1.4 to 20.6) 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) DISCUSSION In this prospective. The overall clinical success rates were 93. respectively (95% CI.5) (0.5) 1 2 0 1 0 0 0 0 1 0 0 0 (0.9% of whom were at least 75 years old. the present study is the first comparative evaluation of 2 different fluoroquinolones in hospitalized elderly patients with CAP.9) [19]. and diabetes mellitus. 175 years).7% (77 of 92 patients) for the oral and intravenous comparator arms. clinical cure rates in the moxifloxacin arm were consistently higher than.2 (0.0) 6 7 3 1 1 1 1 1 0 1 1 1 (3.5) (0. However.0 1. and amoxicillin/ clavulanate with or without clarithromycin in the intravenous treatment studies [19]. respectively (95% CI.1 .5) 4 (2.0 1. Recently. and 86.6) 15 (7.5) (0.1) 15 (7.6) 3 (1. chronic lung disease.Table 3. Overview of adverse events for hospitalized elderly patients eligible who received moxifloxacin or levofloxacin for the treatment of community-acquired pneumonia.7 years.1) 45 (22. although the incidence of drug-related adverse events was similar to that in the levofloxacin group.0% (53 of 57 patients) and 90.4 7.5) (0.6) 7 (3. those for levofloxacin.2 to 15.2% (83 of 92 patients) for the oral and intravenous moxifloxacin arms.9). levofloxacin.5 11 (5. Clinical trials involving adults have demonstrated that moxifloxacin is effective against CAP [15–18].

Bayer Pharmaceuticals. Financial support. Pfizer. and the National Institutes of Health. possible for most patients. Daniel Lee. GlaxoSmithKline. Potential conflicts of interest. An important limitation of this study is that the etiology of CAP could not be identified in the majority of patients. John Gezon. sequential intravenous/oral moxifloxacin monotherapy provided significantly higher clinical recovery rates by day 3–5 after initiation of treatment and was as effective. Stuart Simon. Rashmikant Kothari. difficile colitis [21] and may reduce the effectiveness of subsequent antimicrobial therapy [22]. Robert Aris. William Salzer. R.0% vs. difficile diarrhea than levofloxacin therapy [21]. Wyeth.H. MEMBERS OF THE STUDY GROUP The Community-Acquired Pneumonia Recovery in the Elderly Study Group included the following investigators: Jack Bernstein. which range from 10% to 40% [1. including Boehringer Ingelheim. Bernard Feinberg. 2. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. One study in a long-term care facility showed that gatifloxacin therapy may be associated with a higher rate of C.. Charles Andrews. Lillian Oshva. It is possible that the higher rate of adverse events due to any cause was caused by high rates of underlying comorbid illness. In conclusion.. GlaxoSmithKline. there were more occurrences of C. Diarrhea and oral candidiasis were the 2 most commonly reported drugrelated adverse events in both treatment groups. Thus. Randy Dotson. antimicrobial susceptibility data were not available for all cultured organisms. Sanofi-Aventis. Statistical analysis was performed by Bayer Pharmaceuticals. Gary Foley. Pfizer. Marvin Bittner. Lilly. Alvin Teirstein. Boomer. William Reiter. This difference may be due to the eligibility criteria for this study. Adrian James. Aldona Baltch. Monroe Karetzky. M. Kathleen Casey. P ! . Michael Milam. has received honoraria or consulting income from Bayer. 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. Ata Motamedi. Larsen. Donald Graham. correlation of clinical outcomes with bacteriologic outcomes was not 80 • CID 2006:42 (1 January) • Anzueto et al.C. Judy Stone. Kim Scholfield. However. Stienecker.A. Pneumococcal urine antigen testing and serologic testing for detection of atypical organisms were not performed. Richard Kohler. 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. There was no evidence that moxifloxacin therapy increased the risk of Clostridium difficile diarrhea in elderly patients more than levofloxacin did.5%]).e. .A.2). and Altana. Mazhar Javaid. R.resolution of pneumonia than levofloxacin therapy in elderly patients (i. A. although the difference was not statistically significant (P p .N. A.A. William Rodriguez. and Altana. Gerry SanPedro. and the University of Texas Health Science Center at San Antonio was paid for conducting the clinical trial. and the fact that the total duration of hospitalization in this patient population could have been influenced by other factors. Steven Knoper. Theravance. Michael Parry. Derek Knight. Ralf Joffe. Bayer Pharma. Gregory Seymann. Priscilla Sioson. has participated as a speaker in scientific meetings or courses organized and financed by various pharmaceutical companies. Gary Hunt. Chiron. Wyeth-Ayerst. Clark Gillett. Arunabh. Twenty-six patients died during the observation period. Mark Bochan. at least in part. and W. Hite.1 ). The organisms isolated most commonly were Streptococcus pneumoniae.S. has been a consultant for Boehringer Ingelheim. including multiple comorbidities present in these patients. Colby Grossman. L. Dennis Abella. Daniel Lorch. Jonathan Maisel. 8]. Pfizer. there were no differences in duration of stay or duration of intravenous therapy between the 2 regimens. Aventis. Elan. is an employee of Bayer Pharmaceuticals. Jr. Recent publications suggest that fluoroquinolones may increase the risk of C. Douglas Katula. James Tan. and Aerogen. Manuscript preparation. Peter Vrooman. between days 3 and 5 after the start of therapy) may be clinically important. Richard Wunderink. Henry Covelli. Bayer. The rate of treatment-emergent adverse events was significantly higher in the moxifloxacin arm. Wyeth. Schering Plough. 3. The mortality rate in this study is lower than those reported elsewhere for hospitalized patients with CAP. BART. safe. was the principal investigator on this study. 7. Bayer Pharma. S. in the current study. Merck. 8]. Arnold Lentnek.0%]) than in the moxifloxacin arm (1 patient [0. However. This could. All other authors: no conflicts. Philip Giordano. and well tolerated as intravenous/oral levofloxacin monotherapy in hospitalized elderly patients with CAP. Michael Habib. Michael Natalino. which excluded patients who required mechanical ventilation or vasopressors or who had multiorgan failure. Lala Dunbar. Steven Berman. Moxifloxacin-treated patients experienced fewer drug-related cardiac adverse events than did levofloxacin-treated patients. although this difference was not statistically significant (1. Prospective studies are needed to identify the factors associated with duration of antibiotic therapy and hospital stay in this patient population. Marcus Zervos. Sanofi-Aventis. Mark Metersky. be due to the minimum duration of therapy (5 days) mandated by the protocol for patients to be considered for the clinically valid population. compared with the levofloxacin arm. difficile colitis in the levofloxacin arm (6 patients [3. as reported by other investigators [2.5%. Linda Edwards. Acknowledgments We thank James Song for performing statistical analysis. the rates of drug-related and serious adverse events were similar for both treatment arms. Haemophilus influenzae. A. Also. it should be noted that. Timothy Jackson. including cardiac disease. most deaths were associated with the severity of comorbid diseases. and Staphylococcus aureus.

Severe community-acquired pneumonia in the elderly: epidemiology and prognosis. 20: 820–37. Moxifloxacin vs. Pneumonia: still the old man’s friend? Arch Intern Med 2003. Sample size for K 2 2 tables in equivalence studies using Cochran’s statistic. version 8. 3. Fine MJ. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Welte T. Clin Ther 1998. Schurmann D. Torres OH. N Engl J Med 1997. et al. Carson CA. 8. Church D.References 1. et al. et al. 1999. Unger A. 128: 3398–406. 19. Outcome predictors of pneumonia in elderly patients: importance of functional assessment. Clin Infect Dis 2004. Niederman MS. IL). et al. Grossman C. Kumar A. 23: 723–8. Chest 2005. JAMA 1996. 20. Efficacy and safety of moxifloxacin vs clarithromycin for community-acquired pneumonia. Alvarez B. SAS/STAT user’s guide. 336:243–50. 7. Haverstock D. Clin Infect Dis 2003. et al. 38:640–5. Rello J. Clin Infect Dis 1996. Dowell SF. Fine MJ. Kaplan V. In: Program and abstracts of the 40th Annual Meeting of the Infectious Diseases Society of America (Chicago. 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. short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. A prediction rule to identify low13. The CAPRIE Study Group. Indicators of recurrent hospitalization for pneumonia in the elderly. 37:752–60. 46:1746–54. Antimicrob Agents Chemother 2002. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. 14. Jackson ML. Gaynes R. 9:526–30. Clin Infect Dis 2003. 4. Reimnitz P. Griffin MF. Wunderink RG. Wassell JT. Niederman MS. 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. et al. Neuzil KM. Song JX. 24:378–89. 2. 12. Anzueto A. Brewer T. 52:1603–9. 2002:75. Alexandria. File TM. Morganorth J. Niederman MS. Efficacy of po and iv moxifloxacin in the treatment of community-acquired pneumonia (CAP) in the very elderly (age 175 years) [abstract 172]. et al. DiMarco J. 163:1730–54. Pneumonia in the elderly (geriatric) population. Habib MP. A randomized trial comparing the cardiac rhythm safety of moxifloxacin vs levofloxacin in elderly patients hospitalized with community-acquired pneumonia. antimicrobial therapy. Guidelines for the management of adults with community-acquired pneumonia: diagnosis. Choudhri S. Gough M. and prevention. VA: Infectious Diseases Society of America. 163:317–23. Williams J. Mandell LA. Study Group for Severe Community-Acquired Pneumonia. Yealy DM. Petermann W. Clin Microbiol Infect 2003. 16:748–63. El Solh AA. 10. Today’s Ther Trends 2001. Janssens JP. Okada M. McCombs J. 37:1405–33. et al. Infect Med 1999. Clin Infect Dis 2004. Outbreak of Clostridium difficile infection in a long-term care facility: association with gatifloxacin use. Schaumann R. et al. Control Clin Trials 2003. et al. Munoz J. The cost of treating community-acquired pneumonia. SAS Institute. Bashir O. Choudhri SH. 6. J Am Geriatr Soc 2004. et al. risk patients with community-acquired pneumonia. 18. Kruesmann F. Rimland D. Ackermann G. Dunbar LM. 52:2010–5. 21. Tang-Feldman YJ. 19: 251–70. 11. Clin Infect Dis 2005: 41:1697–705. Popovian R. Safety and efficacy of sequential (iv to po) moxifloxacin for the treatment of community-acquired pneumonia in hospitalized patients. Rodriguez R. 275:134–41. 16. Mandell LA. The burden of community-acquired pneumonia in seniors: results of a population-based study. Curr Opin Pulm Med 2005. J Am Geriatr Soc 2004. Bauer TT. 17. 22. Cary. 5. Schuermann D. High-dose. Anzueto A. Thompson WW. Fogarty C. et al. Bartlett JG. Finch R. 11:226–30. Fogarty CM. Jubert P. Am J Respir Crit Care Med 2001. The MOXIRAPID Study Group. Levofloxacin for CAP in Elderly Patients • CID 2006:42 (1 January) • 81 . Clermont G. Haverstock D. Auble TE. Ruiz D. Larsen SL. Smith MA. Antecedent use of fluoroquinolones is associated with resistance to moxifloxacin in Clostridium difficile. 9. NC: SAS Institute. 15. Killum E. 39:1642–50. Collins O. assessment of severity.

The corrected sentence should read as follows: “The functional consequence of the UL97 mutations is impaired phosphorylation of ganciclovir in virus-infected cells. All rights reserved. Kallas WM. Clinical Infectious Diseases 2006.00 1350 • CID 2006:42 (1 May) • ERRATA . 42:1350 2006 by the Infectious Diseases Society of America. 286]. with the consequent lack of synthesis of ganciclovir triphosphate. and 1 strain from a patient in the levofloxacin arm was intermediate (moxifloxacin MIC. Restrepo MI. In an article published in the 15 May 2002 issue of the journal (Mylonakis E. Choudhri SH. Clin Infect Dis 2006. The footnote should read “Six strains were fluoroquinolone susceptible.”) The authors regret this error. Clin Infect Dis 2002. 34:1337– 41). an error appeared in the third sentence of the third paragraph of the Discussion section. 4 mg/L). and 1 strain from a patient in the levofloxacin arm was intermediate (levofloxacin MIC. 42:73–81). the active form of the drug” [4. Pearle J. the active form of the drug [4]. Heyder A. Community-Acquired Pneumonia Recovery in the Elderly Study Group. not The functional consequence of the UL97 mutations is impaired phosphorylation of ganciclovir in virus-infected cells. Fishman JA. Community-aquired pneumonia recovery in the elderly (CAPRIE): efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy. 4 mg/L)” (not “Six strains were fluoroquinolone susceptible. p. an error appeared in footnote b in table 2. Niederman MS. 1058-4838/2006/4209-0027$15. Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients.E R R ATA In an article published in the 1 January 2006 issue of the journal (Anzueto A. The authors regret this error. with the consequent lack of synthesis of ganciclovir triphosphate.

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