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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 . 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 . Thus, ∼1 in 20 persons aged 85 years experiences a new CAP episode each year . Approximately 40% of CAP episodes among elderly persons require hospitalization . A mortality rate of 40% within 1 year after hospitalization has been reported . 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 (Anzueto@uthscsa.edu). 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
Thus. mechanical endobronchial obstruction. regardless of peripheral WBC count) or leukopenia (total WBC count of !4500 cells/mm3). 400 mg once daily. Cultures were performed if Gram staining revealed 10 squamous epithelial cells per low-power ﬁeld and 25 leukocytes per low-power ﬁeld. After stratiﬁcation by disease severity with the revised American Thoracic Society criteria (mild/moderate vs. and a WBC count of 10. no prospective clinical trials have been published that compare ﬂuoroquinolones in hospitalized elderly patients with CAP. known or suspected active tuberculosis or endemic fungal infection. ﬂuids. chronic therapy (duration of 2 weeks) with immunosuppressant therapy (115 mg/day of systemic prednisone or equivalent). Sputum samples were collected before study drug was started. and at the test-of-cure visit (between days 5 and 21 after the end of therapy). comparative study was conducted from November 2002 to April 2004 at 47 study centers in the United States. previous history of tendinopathy with quinolones. a requirement for initial parenteral therapy. Blood specimens were obtained at enrollment. Patients could be switched to oral therapy at the investigator’s discretion (moxiﬂoxacin.2 F]. rigors and/or chills. systemic antibacterial therapy for 124 h within 7 days of enrollment unless therapy failed after receiving 172 h of a nonﬂuoroquinolone antibiotic. The study was conducted in accordance with the Declaration of Helsinki. pleuritic chest pain. need for mechanical ventilation. 65 years) with clinical signs and symptoms of CAP. known prolongation of the corrected QT interval or use of class IA or class III antiarrhythmics. Patients were also assigned a Pneumonia Outcome Research Team pneumonia severity index score . or known hypersensitivity to study medications. A separate publication involving this same patient population and protocol describes the primary safety variable (i. and could tolerate oral food. neutropenia (neutrophil count of !1000 neutrophils/mL). Patient population. fever (an oral temperature of 38 C [100. or a tympanic temperature of 38. for 7–14 days. A urinary antigen test for detection of Legionella pneumophila was performed. renal impairment (serum creatinine clearance rate of !20 mL/min). 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). 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. However. radiologically conﬁrmed evidence of a new and/or progressive inﬁltrate(s).5 C [101. 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.e. severe hepatic insufﬁciency (Child-Pugh classiﬁcation of C). Additional sputum specimens were obtained from patients with clinical failure.2 F]). known HIV infection (CD4 cell count of !200 cells/mm3). Clinical and bacteriologic outcome deﬁnitions. uncorrected hypokalemia. 400 mg once daily. 500 mg once daily. written informed consent was obtained from each patient. implanted cardiac deﬁbrillator. institution of appropriate antibiotic therapy is imperative for elderly patients. cardiac adverse events) . and medications without vomiting or diarrhea. double-dummy. and if results of culture were positive. double-blind. For patients with a documented and/or a calculated creatinine clearance rate of 20–49 mL/min. the intravenous dose of levoﬂoxacin therapy was a 500-mg loading dose. Patients were considered to be eligible for the clinical efﬁcacy . 250–500 mg once daily) after 2 days of intravenous therapy if they demonstrated improvement during intravenous therapy.4 F]. samples were obtained and cultured every 48 h until results were negative. patients were randomly assigned to receive either intravenous moxiﬂoxacin. a rectal temperature of 39 C [102. randomized controlled. and each institution’s internal review board approved the study protocol. 5–8]. 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. A prospective. The trial population included hospitalized elderly patients (age. Clinical signs and symptoms were evaluated before treatment (within 48 h before receipt of the ﬁrst dose of study drug). auscultatory ﬁndings of rales and/or crackles on pulmonary examination and/or evidence of pulmonary consolidation. Patients with any of the following characteristics were excluded from the study: hospitalization for 148 h before pneumonia development.2 F]) or hypothermia (rectal or core temperature of !35 C [95. severe) . Treatment with moxiﬂoxacin did not require dosage adjustment for these patients. Clinical response at the test-of-cure visit (between days 5 and 21 after the end of therapy) was the primary efﬁcacy outcome. Clinical and bacteriologic evaluations. or intravenous levoﬂoxacin. were afebrile for 8 h. 10]. followed by a dosage of 250 mg once daily for 7–14 days. breaths/min). during treatment (between days 3 and 5 after the start of treatment). or levoﬂoxacin. Updated CAP treatment guidelines recommend ﬂuoroquinolone monotherapy or b-lactam plus macrolide combination therapy for hospitalized patients with CAP [9. dyspnea and/or tachypnea (respiratory rate of 120 74 • CID 2006:42 (1 January) • Anzueto et al. PATIENTS AND METHODS Study design and treatment. although it was not used for stratiﬁcation. significant bradycardia (heart rate of !50 beats/min).within 18 months . to prevent unnecessary morbidity and death [3. Accordingly..000 cells/mm3 or 15% immature neutrophils (bands. Both oral medications were encapsulated for blinding.
Moxiﬂoxacin vs. Bac- teriologic responses during therapy and at the test-of-cure visit were deﬁned as eradication. required hospitalization. or otherwise endangered the patient and were documented up to 30 days after receipt of the ﬁnal dose of study drug. Adverse events were documented up to the test-of-cure visit using Medical Dictionary for Regulatory Activities (MedDra) terminology.. Treatment-emergent adverse events (i. The safety analysis included patients who received at least 1 dose of study drug (intention-to-treat population). for enrollment in the clinically valid population) if they met the eligibility criteria. Each adverse event was rated by the investigator on the basis of intensity (mild. received the study drug for 48 h (in cases of clinical failure) or for 5 days (in cases of clinical cure).. and coagulation evaluations and for urinalysis. or indeterminate. resulted in disability. 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. moderate. analysis (i. 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. or indeterminate. or possibly related to the study drug. regardless of their relationship to study drug) and adverse reactions leading to premature discontinuation were recorded. received no other concomitant systemic antimicrobial therapy. 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).e. probably. were life-threatening. and had 80% adherence with study medication. Superinfection was deﬁned as the appearance of a new pathogen in patients with clinical failure. failure (as deﬁned above). failure (failure to respond or insufﬁcient improvement of the signs and symptoms of infection such that additional antimicrobial therapy was required). or severe) and whether it was deﬁnitely.Figure 1. chemistry. presumed persistence (no sputum specimen was available for patients with clinical failure). 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). or indeterminate. Levoﬂoxacin for CAP in Elderly Patients • CID 2006:42 (1 January) • 75 . had a test-of-cure clinical assessment that was not indeterminate. Serial blood and urine samples were collected throughout the study for routine hematologic. Safety and tolerability assessment. presumed eradication (if no sputum specimen was available because of clinical success). Serious adverse reactions were deﬁned as those that were fatal.e. persistence.
06 .2 . The primary efﬁcacy objective was to show that moxiﬂoxacin therapy was not inferior to levoﬂoxacin therapy for the treatment of CAP.8 .7) 77.4 97 (68.6) NOTE.0) 9 (6.7) 123 (87.3 .3) (31.Table 1.1) 19 (13.9) 111 (79.3) .4) 1 (0. 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 .0 .7) 51 (36.9) (19.2 .5) 68 (48. giving a power of 76% by using a D (critical difference) of 10% or a power of 90% by using a D of 15%.7) 10 (7.4) 69 (48.1) 61 (43. as well as bacteriologic outcomes.9) 118 (83. Data on the total duration of hospital stay.0) 57 .1) 10 (7.9) 87 (61.2 Characteristic Male sex Race White Black Hispanic Asian Age.1 65–95 91 (64. a total of 400 enrolled patients provides 280 patients (400 patients 70%) in the clinically valid population.1) 38 (27.9 7.4) 6 (4. duration of intensive care unit (ICU) stay..5) 6 (4.0) 40 (28.1) 107 48 51 27 (76. 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. and duration of intravenous therapy were collected at the test-of-cure visit. 76 • CID 2006:42 (1 January) • Anzueto et al.5 Nursing home residence Smoking history. on the basis of clinical response at the test-of-cure visit for the clinically valid population. total duration of antimicrobial therapy.2) 41 (29.5 . years Mean SD Range 175 Pneumonia severity index score 1–3 4 5 Severe ATS CAP severity scorea P . .6 .7) 12 (8.7) 7 (5.7 65–98 80 (57. Secondary efﬁcacy end points included clinical outcome at other time points in the intention-to-treat and microbiologically valid populations.6) 22 (15.3) (38.5 1.6 . Data are no.7 . Health resource utilization assessment. All statistical analyses were performed using SAS (SAS Institute) . 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). Logistic regression was performed to evaluate treatment effect on the primary dependent efﬁcacy outcome variable (i.4) (19. unless otherwise indicated.8) … 77. The Cochran-MantelHaenszel method was used to calculate 95% CIs .3) 26 (18.5) 11 (7.6) 7 (5. (%) of patients.3) (36.3) 96 (68.4 7.1 102 54 45 27 (72.9 . Statistical analysis.6 .1) 57 (40. According to 2001 guidelines of the American Thoracic Society (ATS) .4) (34. Moxiﬂoxacin arm (n p 141) 69 (48.e.9) 7 (5.7) 25 (17.3) 48 Levoﬂoxacin arm (n p 140) 71 (50.8 .
and treatment groups were compared using 1-way analysis of variance for continuous variables or x2 analysis for categorical data. including sex. switch from intravenous to oral treatment. RESULTS Patient disposition and demographic characteristics. Clinical cure rates at the test-of-cure visit for the clinically valid population. pneumonia severity index score. Clinical recovery during therapy (between days 3 and 5 after the start of treatment). stratiﬁed by community-acquired pneumonia (CAP) severity (A) and age (B). Multiple logistic regression was performed with only those variables with P values of !.1 (P p .9 7. The clinically valid population included 141 patients in the moxiﬂoxacin group and 140 patients in the levoﬂoxacin group.Figure 2. pretreatment hospitalization history. age.7–14. *95% CI for difference. Demographic and clinical characteristics at baseline. Of 401 patients randomly assigned to receive study therapy. and health status.01 ). primary efﬁcacy outcome). 1. race. Moxiﬂoxacin vs. with Figure 3.e. Continuous independent variables were treated as continuous. The clinically valid population had a mean age ( SD) of 77. B. Treatment effect was evaluated after adjusting for other confounding factors in the regression model from the univariate analyses. body mass index.2). clinical response at the test-of-cure visit) after adjusting for risk factors. infection duration. presence of pathogen at baseline. 7 received no study medication.. Clinical cure at the test-of-cure visit (i. primary residence. the safety population included 394 patients (ﬁgure 1). Levoﬂoxacin for CAP in Elderly Patients • CID 2006:42 (1 January) • 77 . Thus. smoking history.9 (P p . adverse events. with no collapsing done for the analysis. Clinical outcomes for the clinically valid population: A. aspiration pneumonia.1 years. Baseline demographic and clinical characteristics for the clinically valid population are summarized in table 1 and were similar between the 2 treatment groups.9 to 11. and laboratory data were summarized using descriptive statistics.20. †95% CI for difference. sequence of intravenous dosing. 1.
by culture site Respiratory Blood Pathogen isolated Streptococcus pneumoniae Haemophilus inﬂuenzae Staphylococcus aureus Pseudomonas aeruginosab NOTE.0% [8 of 16 patients] in the levoﬂoxacin arm).0% in the levoﬂoxacin arm (95% CI.0% in the moxiﬂoxacin arm (17 of 21 patients) and 75. For the clinically valid population.8 4. Serious adverse events were reported for ∼23% of patients in both treatment groups (P p .7–14. One patient had an organism isolated from cultures of respiratory and blood specimens. P p .19.5% and 90.9% of patients in the moxiﬂoxacin arm..22 to 0.01 ) (table 3). Only 6 moxiﬂoxacin.3 in the levoﬂoxacin group. There was no difference in mortality between the 2 treatment groups (P p . 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). (%) of patients Moxiﬂoxacin arm a (n p 21) 17 (81.3) 3 (14.8 2. the total duration of hospital stay ( SD) was 7.7% in the levoﬂoxacin arm (23 of 30 patients) (95% CI.9% for the moxiﬂoxacin arm and 87. eradication or presumed eradication of the causal pathogen) at the test-of-cure visit was 81. Univariate analysis identiﬁed the following risk factors as inﬂuences of clinical outcome (ﬁgure 3): for severe CAP. P p .0% of patients in the levoﬂoxacin arm.5 4.7).1%) of 281 (21 [41.0%. 1. Patients in this population had a mean number of 18. For the clinically valid population. respectively.95 ). with a mean duration ( SD) of 6. and the mean number of pretreatment medications was 6.5) Levoﬂoxacin arm (n p 30) 22 (73. P p .6% in the levoﬂoxacin arm (95% CI. The rate of treatment-emergent adverse events due to any cause was signiﬁcantly higher in the moxiﬂoxacin-treated patients (P p .09 to 0. Health resource utilization..2) (ﬁgure 2). and the rates for those aged 75 years were 94.9 ). There was no difference between treatments with regard to the rate of premature discontinuation owing to an adverse event.7 days for the moxiﬂoxacin arm and 10. 0.6).0 2.3) 9 (30) 7 (23. At the test-of-cure visit.95).9.9 days for the levoﬂoxacin arm (P 1 . The mean duration ( SD) of intravenous therapy was 3. The bacteriologic response was in agreement with the clinical response: clinical cure rates for the microbiologically valid population were 81.7 2.3) 3 (14. Multiple regression analysis using various combinations of risk factors failed to show a statistically signiﬁcant higher cure rate between treatment groups. and patients who were still receiving intravenous therapy at the test-of-cure visit had lower clinical cure rates (55. the primary efﬁcacy outcome) for the clinically valid population was 92.8). There were no differences in health resource utilization between patients with positive versus those with negative results of pretherapy bacterial cultures.9% for the levoﬂoxacin arm (95% CI.14. and all were determined by the investigators to be due to the patient’s comorbid diseases.8) 7 (33.and 3 levoﬂoxacin-treated patients died during therapy or within the ﬁrst 7 days after therapy. the clinical cure rate (i. At the during treatment visit (between days 3 and 5 after the start of therapy) for the clinically valid population. the total duration of hospital stay was similar between the treatment groups. Bacteriologic success (i.5). None of the deaths were considered to be drug related. the mean duration ( SD) of total antimicrobial therapy was 10. 0. compared with 90.0 2.e.3 in the moxiﬂoxacin group and 19.5 4. 17 (48.67).7% in the moxiﬂoxacin arm and 84. although the rates of drug-related and serious adverse events were similar for both treatment arms. 51 (18.1.0) 5 (23. 88. re78 • CID 2006:42 (1 January) • Anzueto et al. 97. 50.1 days and 6.98). the clinical cure rates for those aged 65– 74 years were 90.3) 8 (26. and 1 strain from a patient in the levoﬂoxacin arm was intermediate (moxiﬂoxacin MIC. had achieved clinical recovery (95% CI. 0.9% of patients aged 75 years.8 4. for patient age.2 days in the moxiﬂoxacin arm and 7. P p .3) 2 (9.6% [5 of 9 patients] in the moxiﬂoxacin arm vs. spectively (95% CI.0% in the moxiﬂoxacin arm (17 of 21 patients) versus 76. . a ∼60.2%] in the moxiﬂoxacin arm and 30 [58.0% in the levoﬂoxacin arm (21 of 28 patients) (P p . and the majority of deaths occurred 17 days after receipt of the ﬁnal dose of study drug.12 to 0. P p .32. Safety and tolerability.5). The majority of patients were switched to oral therapy on day 3 or 4 after the start of therapy (93.6% in the moxiﬂoxacin arm vs.6%) of 35 of these events were considered to be drug related (10 in the moxiﬂoxacin arm and 7 in the levoﬂoxacin arm).2 days for levoﬂoxacin arm (P p .7) Variable Positive culture result.0.8 comorbidities (18. Of the patients in the clinically valid population.8%] in the levoﬂoxacin arm) had 59 baseline pathogens identiﬁed in sputum or blood specimens and constituted the microbiologically valid population (table 2).0 days for the moxiﬂoxacin arm versus 3. 0.e. P p . Clinical outcomes. for hospital stay after the initiation of study drug treatment (P p .3) 5 (16.01) (ﬁgure 2).0% in the moxiﬂoxacin arm and 85.7) 10 (33. 4 mg/L). Bacteriologic outcomes. No.6% in the levoﬂoxacin arm. the rates of clinical cure were 94.31.05 to 0.6 days.6 days in the levoﬂoxacin arm (P p .2).Table 2.4).9).9 to 11. No clinically signiﬁcant differences between treatment groups were seen for clinical laboratory test values or vital signs. All patients had negative results of urinary antigen tests for detection of Legionella pneumophila. b Six strains were ﬂuoroquinolone susceptible. P p . 1. For patients in the ICU. P p .
There was a higher incidence of adverse events due to any cause in the moxiﬂoxacin group. Clinical trials involving adults have demonstrated that moxiﬂoxacin is effective against CAP [15–18].  reported similar efﬁcacy and safety outcomes between 2 levoﬂoxacin doses (500 mg vs. randomized. The overall clinical cure rate and bacteriologic success rates were similar between the 2 treatment groups. although the incidence of drug-related adverse events was similar to that in the levoﬂoxacin group. respectively (95% CI.0 1.4% (38 of 44 patients) and 83.5) DISCUSSION In this prospective. In subgroup analyses based on CAP severity and patient age. The overall clinical success rates were 93.5) (0.5) (0. Levoﬂoxacin for CAP in Elderly Patients • CID 2006:42 (1 January) • 79 . including cardiac.5) (0. Dunbar et al. 3.7) 46 (23.4) 20 (10. moxiﬂoxacin-treated patients were more likely to have clinical improvement by treatment day 3–5 than were levoﬂoxacin-treated patients.9% of whom were at least 75 years old.7) 51 (26. respectively (95% CI. and 86.5 . and diabetes mellitus.7 years.5) 4 (2. levoﬂoxacin. 175 years).6) 11 (5. clinical cure rates in the moxiﬂoxacin arm were consistently higher than.1) 45 (22. No.5) (0.4 to 20.5) 45 (22.6) 15 (7. randomized. Overview of adverse events for hospitalized elderly patients eligible who received moxiﬂoxacin or levoﬂoxacin for the treatment of community-acquired pneumonia. 60.5 11 (5.5) (0.0) (0.1) 15 (7. The pneumonia severity index score is high for this population probably because this measure is strongly inﬂuenced by age . and amoxicillin/ clavulanate with or without clarithromycin in the intravenous treatment studies .4 7.6) 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 11.6) 7 (3.5% 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 . In very elderly patients with CAP (age.9).9) . controlled trials of intravenous and oral moxiﬂoxacin therapy found similar efﬁcacy and adverse event rates to those observed in the current trial .2) Levoﬂoxacin arm (n p 199) 146 (73. gastrointestinal.2% (83 of 92 patients) for the oral and intravenous moxiﬂoxacin arms. chronic lung disease.5) 1.5) (1. a pooled analysis of 5 prospective.5) (0. Comparator agents were clarithromycin and amoxicillin in the oral treatment studies and trovaﬂoxacin.5) (0.5) 10 (5.0) 7 (3.0) 6 7 3 1 1 1 1 1 0 1 1 1 (3. Most patients had concomitant comorbid conditions. 5.5) 1 2 0 1 0 0 0 0 1 0 0 0 (0. This trial included 394 elderly patients with a mean age ( SD) of 77.5) (0.7% (77 of 92 patients) for the oral and intravenous comparator arms. the present study is the ﬁrst comparative evaluation of 2 different ﬂuoroquinolones in hospitalized elderly patients with CAP.5 . 750 mg.2 to 15. (%) of patients Moxiﬂoxacin arm (n p 195) 164 (84.0) (3.01 . Recently. although not statistically signiﬁcantly different from. More than two-thirds of patients in both groups had a pneumonia severity index score of 3. The ﬁnding that moxiﬂoxacin therapy led to a signiﬁcantly more rapid clinical improvement and/or Moxiﬂoxacin vs.9 . once daily) for treatment of mild or severe CAP in adult patients.5) (1.6) 3 (1.0 1.0% (53 of 57 patients) and 90. double-blind trial involving hospitalized elderly patients with CAP.1 . However.Table 3.2 (0. those for levoﬂoxacin.0 .
Financial support. Mazhar Javaid. Daniel Lorch. The mortality rate in this study is lower than those reported elsewhere for hospitalized patients with CAP. Also. Thus. has been a consultant for Boehringer Ingelheim. Larsen. be due to the minimum duration of therapy (5 days) mandated by the protocol for patients to be considered for the clinically valid population. A.N.0%]) than in the moxiﬂoxacin arm (1 patient [0. Jr. All other authors: no conﬂicts. Ata Motamedi. This could. Bayer. Peter Vrooman. Judy Stone. antimicrobial susceptibility data were not available for all cultured organisms. 8]. P ! . Stuart Simon. A. at least in part. Gary Hunt. MEMBERS OF THE STUDY GROUP The Community-Acquired Pneumonia Recovery in the Elderly Study Group included the following investigators: Jack Bernstein. There was no evidence that moxiﬂoxacin therapy increased the risk of Clostridium difﬁcile diarrhea in elderly patients more than levoﬂoxacin did. Adrian James. Priscilla Sioson. Philip Giordano. Daniel Lee. and Altana.resolution of pneumonia than levoﬂoxacin therapy in elderly patients (i. Michael Natalino. including Boehringer Ingelheim. Statistical analysis was performed by Bayer Pharmaceuticals. . An important limitation of this study is that the etiology of CAP could not be identiﬁed in the majority of patients. Clark Gillett. 7. 3.A. including cardiac disease. Lala Dunbar. correlation of clinical outcomes with bacteriologic outcomes was not 80 • CID 2006:42 (1 January) • Anzueto et al. Colby Grossman. Aventis. Elan. Twenty-six patients died during the observation period. Gerry SanPedro. This difference may be due to the eligibility criteria for this study. Potential conﬂicts of interest.5%]). Wyeth. in the current study. Pﬁzer.C.. Schering Plough. Dennis Abella. Stienecker. and W. Gregory Seymann. Prospective studies are needed to identify the factors associated with duration of antibiotic therapy and hospital stay in this patient population. Bernard Feinberg. Michael Parry. James Tan. Mark Metersky.2). difﬁcile colitis  and may reduce the effectiveness of subsequent antimicrobial therapy . William Salzer. William Reiter. John Gezon. Gary Foley. Rashmikant Kothari. Wyeth-Ayerst. has participated as a speaker in scientiﬁc meetings or courses organized and ﬁnanced by various pharmaceutical companies. Charles Andrews. Acknowledgments We thank James Song for performing statistical analysis. One study in a long-term care facility showed that gatiﬂoxacin therapy may be associated with a higher rate of C. Douglas Katula. R. Haemophilus inﬂuenzae. and the National Institutes of Health. Merck. which excluded patients who required mechanical ventilation or vasopressors or who had multiorgan failure.5%. Richard Kohler. Bayer Pharmaceuticals. GlaxoSmithKline. and the University of Texas Health Science Center at San Antonio was paid for conducting the clinical trial. Robert Aris. Chiron. Steven Knoper.H. Kim Scholﬁeld. Steven Berman. Michael Habib. Kathleen Casey. Bayer Pharma. and the fact that the total duration of hospitalization in this patient population could have been inﬂuenced by other factors. Alvin Teirstein.S. Timothy Jackson.0% vs. 2. S. Lillian Oshva. 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. A. Henry Covelli. Linda Edwards. Donald Graham. Recent publications suggest that ﬂuoroquinolones may increase the risk of C. and Altana. difﬁcile colitis in the levoﬂoxacin arm (6 patients [3. sequential intravenous/oral moxiﬂoxacin monotherapy provided signiﬁcantly higher clinical recovery rates by day 3–5 after initiation of treatment and was as effective. 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. The organisms isolated most commonly were Streptococcus pneumoniae. Richard Wunderink. and Staphylococcus aureus. there were more occurrences of C. although the difference was not statistically signiﬁcant (P p . Mark Bochan. Marcus Zervos. However. Theravance. Michael Milam.e. including multiple comorbidities present in these patients. In conclusion. was the principal investigator on this study. Boomer. L. R. Ralf Joffe. Sanoﬁ-Aventis. safe. It is possible that the higher rate of adverse events due to any cause was caused by high rates of underlying comorbid illness. Wyeth. BART. most deaths were associated with the severity of comorbid diseases. Pﬁzer. Aldona Baltch. M. Manuscript preparation. Monroe Karetzky. difﬁcile diarrhea than levoﬂoxacin therapy . is an employee of Bayer Pharmaceuticals. Derek Knight. Bayer Pharma. and well tolerated as intravenous/oral levoﬂoxacin monotherapy in hospitalized elderly patients with CAP. compared with the levoﬂoxacin arm. has received honoraria or consulting income from Bayer. it should be noted that. Hite. Marvin Bittner. between days 3 and 5 after the start of therapy) may be clinically important.A. Arunabh.1 ). The rate of treatment-emergent adverse events was signiﬁcantly higher in the moxiﬂoxacin arm. William Rodriguez. Sanoﬁ-Aventis. although this difference was not statistically signiﬁcant (1. and Aerogen. the rates of drug-related and serious adverse events were similar for both treatment arms. Pﬁzer. GlaxoSmithKline. Diarrhea and oral candidiasis were the 2 most commonly reported drugrelated adverse events in both treatment groups. Lilly. possible for most patients. as reported by other investigators [2.. Pneumococcal urine antigen testing and serologic testing for detection of atypical organisms were not performed. Arnold Lentnek. Moxiﬂoxacin-treated patients experienced fewer drug-related cardiac adverse events than did levoﬂoxacin-treated patients. does not have a ﬁnancial relationship with a commercial entity that has an interest in the subject of this manuscript. Randy Dotson. which range from 10% to 40% [1. However.A. 8]. there were no differences in duration of stay or duration of intravenous therapy between the 2 regimens. Jonathan Maisel.
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Pearle J. Kallas WM.00 1350 • CID 2006:42 (1 May) • ERRATA . an error appeared in the third sentence of the third paragraph of the Discussion section.E R R ATA In an article published in the 1 January 2006 issue of the journal (Anzueto A. 4 mg/L)” (not “Six strains were ﬂuoroquinolone susceptible. p. Clin Infect Dis 2006. Clin Infect Dis 2002. 42:73–81). The corrected sentence should read as follows: “The functional consequence of the UL97 mutations is impaired phosphorylation of ganciclovir in virus-infected cells. an error appeared in footnote b in table 2. Choudhri SH. 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. with the consequent lack of synthesis of ganciclovir triphosphate. Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients. Community-aquired pneumonia recovery in the elderly (CAPRIE): efﬁcacy and safety of moxiﬂoxacin therapy versus that of levoﬂoxacin therapy. the active form of the drug . with the consequent lack of synthesis of ganciclovir triphosphate. 4 mg/L). Heyder A.”) The authors regret this error. Niederman MS. 34:1337– 41). and 1 strain from a patient in the levoﬂoxacin arm was intermediate (moxiﬂoxacin MIC. the active form of the drug” [4. The footnote should read “Six strains were ﬂuoroquinolone susceptible. 286]. and 1 strain from a patient in the levoﬂoxacin arm was intermediate (levoﬂoxacin MIC. 1058-4838/2006/4209-0027$15. Clinical Infectious Diseases 2006. The authors regret this error. 42:1350 2006 by the Infectious Diseases Society of America. All rights reserved. Restrepo MI. Fishman JA. In an article published in the 15 May 2002 issue of the journal (Mylonakis E.
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