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Multicenter, Open-Label, Randomized Study to Compare the Safety and Efficacy of Levofloxacin versus Ceftriaxone Sodium and Erythromycin Followed by Clarithromycin and Amoxicillin- Clavulanate in the Treatment of Serious Community-Acquired Pneumonia in Adults.

Kahn, Multicenter, Open-Label, Randomized Study to Compare the Safety and Efficacy of Levofloxacin versus Ceftriaxone Sodium and Erythromycin Followed by Clarithromycin and Amoxicillin- Clavulanate in the Treatment of Serious Community-Acquired Pneumonia in Adults, Clinical Infectious Diseases , Volume 38, Issue Supplement_1, January 2004, Pages S16–S23, https://doi.org/10.1086/378406.

This randomized, multicenter, phase IV, comparative trial, which was designed to show equivalence, compared the efficacy of levofloxacin with

that

of a ?-lactam-macrolide combination in the treatment of 269 seriously ill patients with community-acquired pneumonia.

Patients were randomly assigned to 1 of 2 treatment arms: (1) levofloxacin, 500 mg intravenously, followed by oral administration, every 24 h for 7–14 days, or (2) ceftriaxone sodium, 1–2 g intravenously or intramuscularly

every

24 h, with erythromycin, 500–1000 mg intravenously every 6 h, and then switched to amoxicillin-clavulanate, 875 mg orally twice daily, with clarithromycin, 500 mg orally twice daily for 7–14 days. Among patients evaluable for clinical efficacy, 89.5% of levofloxacin-treated patients (85 of 95 patients) and 83.1% of comparator-treated patients (74 of 89 patients) achieved clinical success (a cure or an improved condition). Both levofloxacin and the comparator were safe and well tolerated, with gastrointestinal disorders being the

most

common adverse event in both groups.

Levofloxacin was as efficacious as the?-lactam-macrolide combination in the treatment of seriously ill patients

with

community-acquired pneumonia. Community-acquired pneumonia (CAP) continues to be a prevalent infection, with an estimated 4 million cases occurring each year in the United States, resulting in >500,000 hospital admissions annually [ 1]. Among Americans ?65 years old, pneumonia is the fifth leading cause of death [ 2].

Standard empirical therapy for patients admitted to the general hospital ward includes the use of broad-spectrum antibacterial agents, which, in many cases, includes a second- or third-generation cephalosporin combined with a macrolide. However, alternative therapies that provide similar antibacterial coverage may also be appropriate. Levofloxacin is a fluoroquinolone that is indicated for the treatment of severe CAP, including CAP due to penicillin-resistant Streptococcus pneumoniae and Legionella pneumophila.

The present study examines the safety and efficacy of levofloxacin monotherapy, compared

with

the

safety and efficacy associated with the combination of a ?-lactam and amacrolide, for the treatment of seriously ill patients with CAP. Adult patients with signs and symptoms of CAP who met ?3 American

Thoracic

Society criteria for in patient treatment were included in the study [ 3]. In addition, all patients included in the study required mechanical ventilation or

had

?2 of the following: fever (oral

temperature

, ?39°C) or hypothermia (oral temperature, ?35.5°C), arespiratory rate of >30 breaths/min, systolic hypotension (systolic blood pressure, 4]. Repeat assessments were to be done on study days 2–4, at 5–7 days after therapy (i.e., at the “test-of-cure visit”), and at 1 month after therapy.

Each study patient provided a sputum specimen for Gram stain and culture.

Acceptable specimens included deep expectorated or suctioned sputum; transtracheal aspirates; bronchial brushings, washings, and biopsy samples; and pleural fluid. Two sets of blood samples for culture were obtained at admission.

If blood cultures performed at the time of admission yielded positive results, the cultures were repeated at subsequent visits. Testing for a typical pathogens at baseline included serologic testing for L. pneumophila, Chlamydia pneumoniae , and Mycoplasma pneumoniae; culture of respiratory fluids for L. pneumophila; culture of nasopharyngeal samples for C. Inclusion of a typical pathogens on the basis of serological findings was based on the following standard laboratory criteria: for L.

pneumophila , a single IgM or

IgG

ELISA titer of >1:256 or a 4-fold increase or decrease in the titer at follow-up 3–4 weeks after therapy (5–6 weeks after study admission); for C.

pneumoniae , a 4-fold increase or decrease in the microimmunofluorescence IgM or IgG titer at follow-up 3–4 weeks after therapy (5–6 weeks after study admission); and, for M. pneumoniae , either a single IgM ELISA titer of >1:16 or a 4-fold increase or decrease in the titer at follow-up 3–4 weeks after therapy (5–6 weeks after study admission); a single IgG ELISA titer of>1:128 or a 4-fold increase or decrease in the titer at 3–4 weeks

after

therapy (5–6 weeks after study admission).

Susceptibility testing was done by broth microdilution. The results for each study drug (levofloxacin, ceftriaxone, erythromycin, clarithromycin, and amoxicillin-clavulanate) were to be categorized as “susceptible,” “intermediate” (i.e., moderately susceptible), “resistant,” or “unknown.” Current National Committee for Clinical Laboratory Standards break points for each agent were used to determine susceptibility [ 5]. The primary efficacy variable was clinical response at the visit that occurred 5–7 days after therapy (i.e., at the test-of-cure visit). On the basis of actual visit data, this measure was expanded to 3–12 days after therapy, for purposes of analysis.

"Clinical response" was defined either as a cure or an improved condition (i.e., as clinical success) or as failure.

“Cure” was defined as resolution of pretreatment clinical signs and symptoms and no further requirement for antimicrobial therapy for CAP. “Improvement” was defined as clinical findings that subsided significantly, albeit with incomplete resolution of clinical evidence of infection in a subject who required no further antimicrobial therapy for CAP.

“Failure” (i.e., presumptive microbiological failure [final culture not obtained]) was defined as no

apparent

response to therapy or as an incomplete response

requiring

additional antimicrobial

therapy

for CAP.

The secondary efficacy variables included the microbiological response, according to pathogen, at the test-of-cure visit; transition in signs and symptoms during therapy; and clinical response at the visit that occurred 1 month after therapy for patients considered to have clinical success at the test-of-cure visit. A total enrollment of 212 patients was expected to yield 79 clinically evaluable patients in each treatment group.

With 79 patients per treatment group, there was an 80% power to demonstrate equivalence between the 2 treatment regimens (under the assumption of an 87% clinical success rate for both arms, with a significance level of .025).

The intent-to-treat population comprised all patients who were randomized and took ?1 dose of study drug.

A patient was considered to be clinically evaluable unless he or she (1) had an unconfirmed diagnosis; (2) was lost to follow-up; (3) did not take?1 dose of study drug; (4) had an insufficient course of therapy; (5) received concomitant or post therapy treatment with another effective systemic antimicrobial agent before the assessment that occurred 3–12 days after therapy (but was evaluable if he or she was judged to have experienced clinical failure and if all other evaluability criteria were met); (6) received another effective systemicant imicrobial agent ?24 h before admission and did not experience clinical failure (but was evaluable if he or she received such antimicrobial treatment before admission, if he or she experienced clinical failure, and if all other evaluability criteria were met); (7) returned for the post therapy test-of-cure visit outside the 3–12-day post therapy window (but was evaluable if he or she discontinued study drug because of

clinical

failure, regardless of the time of any visits, provided that all other evaluability criteria were met); or (8) had other significant protocol violation(s). Patients were considered to be microbiologically evaluable if they were clinically evaluable, if their infection was bacteriologically proven, and if they had an appropriate bacteriologic culture.

For purposes of efficacy analysis, 2-sided 95% CIs around the difference in clinical success rates were generated.

To establish that levofloxacin was at least as effective as the comparator, the upperbound of the confidence interval must have been?15 percentage points. A safety analysis, which included all enrolled patients who took study drug, was done for adverse event data.

A total of 269 patients were enrolled in the study.

The disposition of enrolled patients is shown in figure 1.

Ninety-five of 132 patients who received levofloxacin were clinically evaluable, compared with 89 of 137 patients who were treated with the comparator ( figure 1 and table 1).

Disposition of patients in levofloxacin and comparator treatment arms in a study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia. a Two patients who were randomized to receive levofloxacin

received

treatment with the comparator and were analyzed with the comparator group.

b Reasons for premature discontinuation of therapy are shown in table 1. Disposition of patients in

levofloxacin

and comparator treatment arms in a study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia.

a Two patients who were randomized to receive

levofloxacin

received treatment with the comparator and were analyzed with the comparator group. b Reasons for premature discontinuation of therapy are shown in table 1. Reasons for premature discontinuation of therapy ina study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia. Reasons for premature discontinuation of therapy ina study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia. The demographic characteristics of the 2 treatment groups were comparable and are presented in table 2.

In general, the demographic and baseline characteristics of the clinically evaluable and intent-to-treat populations were comparable. Demographic characteristics of participants (intent-to-treat population) in a study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia. Demographic characteristics of participants (intent-to-treat population) in a study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia. Mean APACHE IIscores were comparable for both treatment

groups

(they were 15.9 for patients in the levofloxacin arm and 16.0 for patients in the comparator arm). These scores confirmed that patients who were entered into the study were seriously ill ( table 3).

APACHE II scores and components of the APACHE II score (for the intent-to-treat population) in a study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia.

APACHE II

scores

and components of the APACHE II score (for the intent-to-treat population) in a study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia.

The duration of therapy (oral or iv) in the safety-evaluable population (which is the same as an “intent-to-treat” population) was a mean (±SD) of 10.74± 4.29 days for patients treated with levofloxacin and a mean (±SD) of 10.02 ± 4.66 days for patients treated with the comparator. The median duration of therapy for levofloxacin- and comparator-treated patients was 13.0 and 11.0 days, respectively. The average number of days until the switch from iv to oral therapy in the intent-to-treat population was 4.5 days for the levofloxacin group and 5.1 days for the comparator group.

Clinical success was achieved in 89.5% of clinically evaluable patients (85 of 95 patients) treated with levofloxacin and in 83.1% of clinically evaluable comparator-treated patients (74 of 89 patients) (95% CI, ?16.8 to 4.2). In the intent-to-treat population, clinical success was achieved in 72.7% of levofloxacin-treated patients (96 of 132 patients) and in 64.2% of the comparator-treated patients (88 of 137 patients) (95% CI, ?19.9 to 2.9)( table 4).

Overall clinical response forintent-to-treat and clinically evaluable patients in a study of the safety andefficacy of levofloxacin in the treatment of community-acquired pneumonia.

Overall clinical response forintent-to-treat and clinically evaluable patients in a study of the safety andefficacy of levofloxacin in the treatment of community-acquired pneumonia.

Among patients with cultures of respiratory samples that yielded positive results for S. pneumoniae , 86.7% of patients treated with levofloxacin (13 of 15

patients

) and 85.0% of patients in the comparator group (17 of 20 patients) demonstrated clinical success.

For patients with Haemophilus influenzae , 100% of

patients

treated with levofloxacin (4 of 4 patients) and 87.5% of patients treated with the comparator (7 of 8 patients) demonstrated clinical success.

pneumoniae , clinical success was demonstrated in 100% of patients in the levofloxacin group (5 of 5 patients) and in 80.0% of patients in the comparator group (8 of 10 patients). For patients with results of serological testing that were positive for any of the 3 a typical pathogens, 96.0% of patients in the levofloxacin group (24 of 25 patients) and 91.2% of patients in the comparator group (31 of 34 patients) demonstrated clinical success ( table 5).

Clinical response rates, after therapy, for clinically evaluable patients with pathogens of primary interest in a study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia, summarized by source. Clinical response rates, after therapy, for clinically evaluable patients with pathogens of primary interest in a study of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia, summarized by source.

Among patients with pneumococcal bacteremia at study entry, clinical success was demonstrated in 77.8% of the levofloxacin-treated clinically evaluable patients (7 of 9 patients) and in 77.8% of the comparator-treated clinically evaluable patients (7 of 9 patients).

There were no cases confirmed by follow-up culture of persistent pneumococcal bacteremia in either group of patients. Thirty-eight patients in the clinically

evaluable

population required mechanical ventilation at study admission because of the severity of their illness. For this group of patients, clinical success was achieved in 84.2% of patients treated with levofloxacin (16 of 19 patients) and in 63.2% of patients treated with the comparator (12 of 19 patients) ( table 6). Clinical response rates among clinically evaluable patients requiring mechanical ventilation at study entry in astudy of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia.

Clinical response rates among clinically evaluable patients requiring mechanical ventilation at study entry in astudy of the safety and efficacy of levofloxacin for the treatment of community-acquired pneumonia.



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