0
Clinical Investigations: INFECTIONS |

Oral Moxifloxacin vs High-Dosage Amoxicillin in the Treatment of Mild-to-Moderate, Community-Acquired, Suspected Pneumococcal Pneumonia in Adults* FREE TO VIEW

Patrick Petitpretz, MD; Pierre Arvis, MD; Miroslav Marel, MD, FCCP; Joaquim Moita, MD; Juan Urueta, MD; the CAP5 Moxifloxacin Study Group
Author and Funding Information

Affiliations: *From the Service de Pneumologie (Dr. Petitpretz), Hôpital André Mignot, Le Chesnay, France; Bayer (Dr. Arvis), Puteaux Paris Cedex, France; Servicio de Pneumologia (Dr. Moita), Centro Hospitalar de Coimbra, Coimbra, Portugal; Department of Pneumonology (Dr. Marel), Faculty Hospital Motol, Charles University, Prague, Czech Republic; Instituto Nacional de Enfermedades Respiratorias (Dr. Urueta), Servicio de Urgencias, Calz de Tialpan, Col. Torriello Guerra, Mexico. ,  A complete list of members of the CAP5 Moxifloxacin Study Group is listed in the Appendix. This was a multicenter study initiated and supported by Bayer AG.

Correspondence to: Patrick Petitpretz, MD, Service de Pneumologie, Hôpital André Mignot, 177 route de Versailles, 78157 Le Chesnay, France; e-mail: ppetitpretz@ch-versailles.fr



Chest. 2001;119(1):185-195. doi:10.1378/chest.119.1.185
Text Size: A A A
Published online

Study objectives: Comparison of the efficacy and safety of moxifloxacin vs amoxicillin for treatment of mild-to-moderate, suspected pneumococcal community-acquired pneumonia (CAP) in adult patients.

Design: Multinational, multicenter, double-blind, randomized study.

Setting: Eighty-two centers in 20 countries (Argentina, Brazil, Chile, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Lithuania, Mexico, Portugal, Russia, Slovenia, South Africa, Spain, Turkey, Ukraine, United Kingdom, and Uruguay).

Patients: Four hundred eleven adults (inpatients or outpatients) with suspected pneumococcal CAP.

Interventions: Randomization 1:1 to moxifloxacin, 400 mg/d, or amoxicillin, 1,000 g tid, for 10 days.

Results: Primary efficacy parameter was clinical response, 3 to 5 days after therapy (end of therapy [EOT]) in the per protocol (PP) population (362 patients). The clinical success rate in the PP population was 91.5% (moxifloxacin) and 89.7% (amoxicillin; two-sided 95% confidence interval, −4.2 to 7.8%). The clinical cure rate in patients with proven pneumococcal pneumonia was similar in both treatment groups (87.8%). The bacteriologic success rate in 136 bacteriologically evaluable patients at the EOT was 89.7% (moxifloxacin) and 82.4% (amoxicillin). The bacteriologic success rate against Streptococcus pneumoniae was 89.6% (moxifloxacin) and 84.8% (amoxicillin). The frequency of adverse events was comparable in both treatment groups. Digestive symptoms were the most common drug-related adverse events in both treatment groups.

Conclusions: Moxifloxacin was statistically at least as effective as high-dose amoxicillin for treatment of mild-to-moderate, suspected pneumococcal CAP. Moxifloxacin may be an alternative for empiric CAP treatment, especially in areas where multidrug resistance in S pneumoniae is sufficiently prevalent to preclude routine penicillin.Key words: amoxicillin; community-acquired pneumonia; moxifloxacin; oral therapy; Streptococcus pneumoniae

Community-acquired pneumonia (CAP) remains a common cause of morbidity throughout the world, with an estimated incidence of 12 cases per 1,000 population per year.12 Since it is a condition with a significant mortality and is a major cost to the health services of all countries, treatment should be as effective as possible. The choice of initial therapy is usually empirical. Treatment of CAP should be straight forward and relatively easy; however, strategies for treatment, as shown in several guidelines, remain controversial and difficult to standardize for all individual and geographic circumstances.36 One of the most important reasons for modification of the established regimens of empirical therapy is related to the variation in the susceptibility patterns of the common pathogens, particularly Streptococcus pneumoniae and Haemophilus influenzae.

The incidence of antibiotic resistance, particularly to β-lactams such as penicillin, in strains of S pneumoniae has increased dramatically over the past few years, and resistant strains have been identified worldwide.78

In contrast to ampicillin, which has minimum inhibitory concentrations (MICs) similar to those of penicillin G, amoxicillin has enhanced activity against penicillin-resistant S pneumoniae.910 Penicillin-resistant strains are also resistant to oral cephalosporins, and all oral cephalosporins are less active than penicillin G or amoxicillin against intermediate and resistant strains. Concurrent resistance to other antipneumococcal antibiotics has been shown in many strains with diminished susceptibility to penicillins and cephalosporins including erythromycin, the newer macrolides (clarithromycin, azithromycin), clindamycin and other tetracyclines, and cotrimoxazole.9,1112

In line with the above findings, the availability of alternative antibacterial agents has become increasingly important. Until recently, empirical therapy with quinolones has not proved popular because of inconsistent coverage of S pneumoniae.13

Moxifloxacin is a broad-spectrum, new-generation, oral fluoroquinolone that is approved for the treatment of various community-acquired respiratory infections. Previous studies1416 have shown that moxifloxacin, in contrast to older fluoroquinolones, has enhanced activity against strains of S pneumoniae in vitro and in vivo, irrespective of susceptibility to penicillin or macrolides. In addition, moxifloxacin is active against other pathogens commonly associated with CAP, including H influenzae, Mycoplasma spp, Chlamydia pneumoniae, and Legionella pneumophila.19

These data, as well as the demonstration that moxifloxacin has a favorable pharmacokinetic profile, diffuses into respiratory tract secretions, and is concentrated in alveolar macrophages,2023 have made it an attractive agent for use in patients with CAP of suspected pneumococcal origin.

The aim of this study was to compare the efficacy and safety of moxifloxacin, 400 mg/d, with amoxicillin, 1,000 mg tid. A 3,000 mg/d dosage of amoxicillin is advocated for first-line use in several countries in Europe, particularly France, in order to ensure adequate blood levels against infection caused by pneumococci with reduced susceptibility to penicillin.5

Study Design

This was a prospective, multinational, multicenter, double-blind, comparative study involving 411 patients with CAP of suspected pneumococcal origin randomized 1:1 to receive either moxifloxacin (400 mg/d) or amoxicillin (1,000 mg tid) for 10 days. Patients were enrolled in 82 centers in 20 countries: Argentina (1 center), Brazil (1 center), Chile (1 center), Croatia (1 center), Czech Republic (6 centers), Estonia (1 center), France (30 centers), Hong Kong (2 centers), Hungary (6 centers), Lithuania (2 centers), Mexico (7 centers), Portugal (3 centers), Russia (7 centers), Slovenia (1 center), South Africa (2 centers), Spain (4 centers), Turkey (2 centers), United Kingdom (2 centers), Ukraine (2 centers), and Uruguay (1 center).

This study was conducted with approval from the ethics committees in each of the countries involved and was monitored according to good clinical practices. Written informed consent was obtained from each patient prior to entry into the study. The first patient entered the study in June 1997, and the last patient completed the study in June 1998.

Study Population

Adult patients (≥ 18 years of age) presenting with CAP of suspected pneumococcal origin were enrolled in the study. Patients were classified as having CAP if they presented with fever (rectal temperature ≥ 38.5°C, oral temperature ≥ 38°C) and radiologic evidence of an infiltrate consistent with pneumonia, and at least one of the following signs or symptoms: cough, purulent sputum, dyspnea/tachypnea (> 20 breaths/min), or auscultatory findings such as rales/rhonchi, indicating pulmonary consolidation. S pneumoniae was suspected of being the causative agent of CAP if at least two of the following criteria were present: rapid onset of symptoms (≤ 48 h); high fever (rectal temperature ≥ 39.0°C, oral temperature ≥ 38.5°C) accompanied by rigors/chills; pleuritic chest pain; localized alveolar consolidation on chest radiograph; or the presence of Gram-positive cocci on direct sputum stain.2425

Patients were excluded from entry to the study if they presented with a history of hypersensitivity to quinolones or penicillins; a previous history of tendinopathy associated with quinolones; suspected aspiration pneumonia due to vomiting; a severe infection requiring parenteral therapy; any other infection necessitating the administration of a concomitant systemic antibacterial agent; concurrent disease considered likely to interfere with the clinical course of the pneumonia; AIDS (although HIV-positive patients could be included); significant renal impairment (serum creatinine level > 265μ mol/L); hepatic disease (alanine transaminase or aspartate transaminase and/or total bilirubin level more than three times the upper limit of normal); and neutropenia (neutrophil count < 1,000 cells/μL). Female patients who were pregnant or lactating or of childbearing potential in whom pregnancy could not be excluded were not eligible for entry into the study. Further exclusion criteria included patients known to have congenital or sporadic syndromes of QTc prolongation, or receiving concomitant medication reported to increase the QTc interval; patients who had been hospitalized for> 48 h before the onset of pneumonia; and patients who received previous therapy with a systemic antibiotic to treat the current episode of pneumonia for > 24 h prior to enrollment. Patients who clearly failed on previous antibacterial therapy (treatment duration> 48 h) might be enrolled if the antibacterial regimen did not contain a fluoroquinolone or a β-lactam.

Study Conduct

Patients were evaluated at the time of enrollment into the study (visit 1); after 3 to 5 days of treatment (visit 2); days 13 to 15 (3 to 5 days after the EOT; visit 3); and at days 31 to 38 of follow-up, 3 to 4 weeks after the EOT (visit 4).

On entry to the study (visit 1), procedures included verification of inclusion and exclusion criteria, informed consent, complete medical history, physical examination including vital signs, ECG, and chest radiograph. Blood and urine samples were collected for laboratory analyses (hematology, blood chemistry, urinalysis, and pregnancy test in women of childbearing potential), serologic testing, pneumococcal antigen detection, and microbiology testing. Treatment was initiated as soon as the inclusion procedures were completed.

Repeated evaluation of symptoms, and physical evaluation including vital signs were performed at visit 2, visit 3, and visit 4; chest radiograph at visit 3 (and at visit 2 and/or visit 4 if clinically indicated); microbiology testing at visit 2 and visit 3 (and/or visit 4 if clinically indicated); laboratory analyses at visit 2 and visit 3 (and at visit 4 if necessary); and serologic testing at visit 4.

The decision for hospitalization was left to the discretion of the investigator. Adverse events and health-care utilization (concomitant medication, diagnostic and therapeutic procedures) were recorded at each visit. Adverse events were classified by the investigator as to severity and relationship to study drug medication. Patients could withdraw from the study at any time at their discretion, or could be discontinued by the investigator for medical or administrative reasons. A final evaluation (signs and symptoms, chest radiograph, cultures, and laboratory testing) was performed prior to withdrawal from the study. Investigators could then administer the drug of their choice, but the patient still had to complete the follow-up visits.

Microbiology

Paired blood samples to detect possible bacteremia were collected at visit 1, prior to initiation of treatment. Bronchopulmonary secretions were collected at visit 1 for bacteriological culture; sputum was collected by deep expectoration; bronchial material by nasotracheal/endotracheal suction, BAL, bronchoscopic-protected catheter or protected specimen brush or transtracheal aspiration; or pleural fluid by aspiration or tap. Respiratory cultures were repeated during therapy and/or at follow-up when clinically indicated. Gram’s stains were performed on all sputum samples and/or bronchial material specimens. Only sputum samples and nasotracheal/endotracheal suction specimens containing < 10 squamous epithelial cells and > 25 leukocytes per low-power field were considered acceptable for culture. A mixed colony count of≥ 106 cfu/mL was required to discriminate bronchial contaminants from organisms considered as causative for pneumonia. The diagnostic thresholds for BAL and bronchoscopic-protected catheter or protected specimen brush corresponded to colony counts of > 104 cfu/mL and 103 cfu/mL, respectively.

All cultured bacterial organisms were identified by genus and species and were classified by the investigator as infecting, colonizing, contaminant, or normal flora. Gram-positive and Gram-negative pathogens were subjected to susceptibility testing to moxifloxacin and amoxicillin, performed by E-test (AB Biodisk; Solna, Sweden) in accordance with National Committee for Clinical Laboratory Standards guidelines. Strains of S pneumoniae were also subjected to susceptibility testing to penicillin by E-test. Plasma and urine samples were collected at visit 1 for detection of pneumococcal antigen by latex agglutination test. Blood samples for serological testing for Mycoplasma pneumoniae, C pneumoniae, Chlamydia psittaci, Coxiella burnetii, and L pneumophila were collected at visit 1 and visit 4. All serologic tests were performed at a centralized reference laboratory (Glarif Cerba; Baillet en France, France).

Efficacy Analysis

All patients who entered the study and who received at least one dose of the study drug were evaluable for the intention-to-treat (ITT) analysis. Patients who met the inclusion/exclusion criteria and were given study medication for a minimum of 48 h (in case of clinical failure) or 5 full days (in case of clinical success) were included in the per protocol (PP) analysis (evaluable population). Efficacy analyses were performed on both the ITT and evaluable population. The primary efficacy variable was clinical response, 3 to 5 days after completion of treatment (visit 3). Clinical response was assessed by the investigator as cure (disappearance of acute signs and symptoms related to infection or sufficient improvement, such that additional or alternative antimicrobial therapy was not required) or failure (insufficient lessening of signs and symptoms of infection, such that additional or alternative antimicrobial therapy was required, or death from the primary diagnosis). Early failures (at visit 2) were classified as failures at both visit 3 and visit 4, and failures at visit 3 were also considered as failures at visit 4.

Clinical success was defined as cure in the evaluable and ITT population. Nonclinical success in the evaluable population was defined as failure or relapse (initial resolution or partial resolution of clinical signs and symptoms within the study drug period, but with subsequent recurrence of clinical condition requiring further antibiotic therapy within the 21 to 28 days after the study drug period). Nonclinical success in the ITT population was defined as failure/relapse, indeterminate (clinical assessment could not be determined), or missing efficacy data.

Patients with at least one causative organism identified in an appropriate pretherapy culture and with an appropriate posttherapy bacteriologic evaluation (positive or negative culture or no material to culture) were included in the bacteriologically evaluable population. Only pathogens considered usual in the culture of respiratory tract secretions (S pneumoniae, H influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, β-hemolytic streptococci, and Staphylococcus aureus) were considered for microbiological documentation in the study. Documentation of infection was also accepted by the presence of a pathogen in blood culture; S pneumoniae antigen in serum and/or urine; and, in the case of atypical pathogens, by a fourfold rise in antibody titers to a value≥ 64 in the case of L pneumophila or a single titer ≥ 8 for IgM M pneumoniae-specific immunofluorescent antibodies, or single titers ≥ 128 for L pneumophila and C pneumoniae and ≥ 64 in IgG M pneumoniae-specific immunofluorescent antibodies.

Bacteriologic response was defined as eradication (initial pathogen was absent during and/or after treatment); presumed eradication (sample collection was no longer possible because the patient had improved clinically and was unable to produce sputum); persistence (reisolation of the original causative organism during or at the end of therapy[ EOT]); presumed persistence (clinical failure without any control culture performed); or superinfection (isolation of a new pathogen during or at the end of study drug treatment that was associated with a recurrence of clinical signs and a new radiologic infiltrate).

Bacteriologic success at the EOT (visit 3) and follow-up (visit 4) was defined as eradication or presumed eradication. Bacteriologic failure at visit 3 was defined as persistence, presumed persistence, or superinfection; at visit 4, as persistence, presumed persistence, eradication with reinfection (eradication of original causative organism by visit 3, but with subsequent reisolation of a new pathogen before or at visit 4 and associated with clinical relapse) or eradication with recurrence (eradication of original causative organism by visit 3, but with subsequent reisolation of the same causative pathogen before or at visit 4 and associated with a clinical relapse).

Safety Analysis

All randomized patients who received at least one dose of study drug were evaluable for safety. Safety evaluations were performed during the whole of the study period (visit 1 to visit 4).

Statistics

All evaluable patients were included in the primary efficacy analysis. An ITT analysis was performed as supportive efficacy analysis. The primary efficacy variable was the clinical response at the EOT. A two-sided 95% confidence interval for the weighted difference between treatment groups in cure rates was constructed using Mantel-Haenszel weights. If, and only if, the lower limit of this confidence interval was > 15%, the moxifloxacin therapy regimen was statistically proven to be not less effective than a standard therapy regimen with amoxicillin. Sample size was based on the assumption of a clinical cure rate of 85% for amoxicillin, with 158 patients per group in order to obtain an 80% probability of including equivalence if both clinical cure rates were truly equal, and a 95% probability of respecting equivalence if amoxicillin was truly superior to moxifloxacin by a 10% greater clinical cure rate. Other efficacy and safety (including laboratory test) data were analyzed using descriptive statistics. Statistical analyses were carried out using the SAS software package (SAS Institute; Cary, NC).

Patients

A total of 411 patients were enrolled into the study. Four hundred eight of 411 patients (99.3%) were included in the ITT and safety analyses (Table 1). Three patients were excluded after randomization, before initiation of study medication: one patient with a hypersensitivity to penicillin, one patient had forbidden concomitant medication (reported to increase QTc interval), and one patient was unable to swallow the encapsulated study medication. Three hundred sixty-two patients (88%) were evaluable for efficacy and safety at the EOT (visit 3). Forty-nine patients were excluded from the PP efficacy evaluation most frequently because of violation of inclusion/exclusion criteria in 16 patients (3.9%) and insufficient duration of therapy in 15 patients (3.6%). Three hundred thirty-eight patients (82%), including all clinical failures carried forward, were valid for efficacy and safety at the EOT and follow-up (visit 4) together. Seventy-three patients were excluded from this combined analysis, most frequently because of violation of inclusion/exclusion criteria in 16 patients (3.9%), insufficient duration of therapy in 15 patients (3.6%), and use of prohibited posttreatment medication in 14 patients (3.4%).

The demographic data, risk factors, and symptoms and signs of pneumonia at inclusion were comparable between the two PP treatment groups (Table 2). Two hundred eighty-five of 362 patients (79%) were hospitalized before therapy, 138 patients in the moxifloxacin group (78%) and 147 patients in the amoxicillin group (79%). Seventy of 362 patients (19%) had preexisting bronchopulmonary disease, 29 of 177 patients (16%) in the moxifloxacin group and 41 of 185 patients (22%) in the amoxicillin group. All evaluable patients had diagnostic findings consistent with pneumonia at the pretherapy chest radiograph: 154 patients in the moxifloxacin group (87%) and 168 patients in the amoxicillin group (91%) had unilateral consolidation, and 17 patients in the moxifloxacin group (10%) and 18 patients in the amoxicillin group (10%) had pleural effusions.

Identification of Pathogens

Causative pretherapy organisms were cultured from 136 of 362 evaluable PP patients (38%), 68 in each treatment group. From examination of respiratory specimens, pneumonia was caused by a single organism in 115 of 126 patients (91.3%) and by two organisms in 11 patients (8.7%). Gram-positive organisms were cultured from specimens from 92 of 126 patients (73%). S pneumoniae was cultured from specimens from 84 patients (66.7%). Gram-negative organisms were cultured from specimens from 44 of 126 patients (34.9%), most commonly H influenzae in 27 patients (21.4%). Organisms cultured from blood samples from 22 patients were S pneumoniae (n = 20), S aureus (n = 1), and K pneumoniae (n = 1). Serologic findings were positive for atypical pneumonia in 29 of 362 evaluable patients (8%), mainly M pneumoniae (n = 20), but also C pneumoniae (n = 6) and L pneumophila (n = 3).

Mixed infections (a positive serologic finding for atypical organisms and causative organism isolated in respiratory and/or blood culture before therapy) were noted in 11 of 362 patients (3.0%). Predominantly, mixed infections were a combination of M pneumoniae and S pneumoniae.

Bacteriologic documentation of S pneumoniae pneumonia is summarized in Table 3. Ninety-eight of 362 evaluable patients (27.1%) had proven pneumococcal pneumonia; 95 cases were documented by culture and 3 were documented only by serum pneumococcal antigen test. Ninety-one strains of S pneumoniae were subjected to susceptibility testing to penicillin. Ten strains (11%) demonstrated high penicillin resistance (MIC > 1μ g/mL), 23 strains (25%) demonstrated intermediate penicillin resistance (MIC, 0.1 to 1.0 μg/mL), and 58 strains (61%) were penicillin susceptible.

The two treatment groups were comparable with regard to baseline bacteriologic findings.

Efficacy

The clinical success rate in evaluable patients at EOT was 91.5% (moxifloxacin) and 89.7% (amoxicillin); at follow-up, 89.4% (moxifloxacin) and 89.3% (amoxicillin). The clinical success rate in the ITT population at EOT was 86.5% (moxifloxacin) and 82.2% (amoxicillin); at follow-up, 77% (moxifloxacin) and 78.9% (amoxicillin; Table 4).

The clinical cure rate in cases of documented pneumococcal pneumonia (positive blood or sputum culture with isolation of S pneumoniae or positive pneumococcal antigen test) was similar for both treatment groups at end of therapy (88% moxifloxacin, 88% amoxicillin) and at follow-up (84% moxifloxacin, 87% amoxicillin; Table 5).

Clinical response in evaluable patients with pneumococcal pneumonia was independent of the results of pretherapy penicillin susceptibility testing in both treatment groups. The clinical cure rate at EOT in patients from whom an intermediately penicillin susceptible S pneumoniae strain (MIC, 0.1 to 1.0 mg/L) was isolated before therapy was 100% (moxifloxacin) and 82% (amoxicillin); in patients from whom a highly penicillin-resistant S pneumoniae strain (MIC, > 1.0 mg/L) was isolated, the cure rate was 86% (moxifloxacin) and 100% (amoxicillin; Table 6).

In the evaluable population, 15 of 177 patients in the moxifloxacin group (8.5%) and 19 of 185 patients in the amoxicillin group (10.3%) had a clinical response of failure at EOT. Twenty of these patients had bacteriologically documented infections at entry into the study: 9 of 15 in the moxifloxacin group (S pneumoniae, n = 6; K pneumoniae, n = 1; Pseudomonas aeruginosa, n = 1; and C pneumoniae, n = 1) and 11 of 19 in the amoxicillin group (S pneumoniae, n = 6; H influenzae, n = 3; L pneumophila, n = 1; M catarrhalis, n = 1; S aureus, n = 1; and Pasteurella multocida, n = 1). Two different organisms were isolated from specimens from two patients at entry to the study. In the moxifloxacin group, only P aeruginosa was still present at the EOT of therapy, although cultures were not repeated in two patients. In the amoxicillin group, S pneumoniae was reisolated from specimens from two patients and H influenzae from one patient.

Superinfection with K pneumoniae was reported in one patient in the amoxicillin group, who presented initially with pneumococcal pneumonia.

Twelve of 15 patients (80%) in the moxifloxacin group and 12 of 19 patients (63%) in the amoxicillin group, who failed to respond to study medication, carried risk factors at entry to the study that were previously associated with treatment failure, including a history of chronic cardiopulmonary disease, diabetes mellitus, and/or more severe pneumonia-related radiographic findings (bilateral pneumonia, multilobar pneumonia, or associated pleural effusion).

The bacteriologic success rate in the evaluable population at the EOT and follow-up was 90% in the moxifloxacin group and 82% in the amoxicillin group (Table 7). The bacteriologic success rate at the EOT was 90% (moxifloxacin) and 85% (amoxicillin; Table 8 ).

A bacteriologic response of failure (persistence, presumed persistence, persistence with superinfection) was recorded at the EOT and at follow-up in 10% and 15% of moxifloxacin-treated patients, respectively, and in 18% of amoxicillin-treated patients at both time points. In the moxifloxacin group, persistence of K pneumoniae was recorded in one patient and presumed persistence of S pneumoniae in five patients and P aeruginosa in one patient. In the amoxicillin group, persistence of S pneumoniae was recorded in three patients, H influenzae in one patient, and presumed persistence of S pneumoniae was recorded in four patients, H influenzae in two patients, S aureus in one patient, M catarrhalis in one patient, and P multocida in one patient.

Pretherapy MIC values against S pneumoniae ranged from 0.023 to 1.5 mg/L for moxifloxacin and 0.016 to 2 mg/L for amoxicillin. The MIC of moxifloxacin against the persistent K pneumoniae increased 0.5 dilution steps from 0.125 mg/L pretherapy to 0.19 mg/L at the EOT. The median MICs of amoxicillin against three persistent S pneumoniae also increased by 0.5 dilution step, from 0.016 mg/L pretherapy to 0.25 mg/L at the EOT; against H influenzae, decreased 0.5 dilution step from 256 mg/L to 0.75 mg/L; and against K pneumoniae remained the same, 256 mg/L.

In the moxifloxacin treatment group, five patients with pneumococcal pneumonia had a bacteriologic response of failure: one patient with a history of chronic bronchitis, chronic cardiac failure, and atrial fibrillation (pretherapy MIC penicillin, 0.023 mg/L; moxifloxacin, 0.38 mg/L); one patient with chronic bronchitis (6 mg/L, 0.5 mg/L), and three patients with no significant medical history (0.016 mg/L, 0.125 mg/L, 0.094 mg/L, 0.19 mg/L, and 0.016 mg/L, 0.064 mg/L, respectively).

In the amoxicillin treatment group, five patients with pneumococcal pneumonia had a bacteriologic response of failure: one patient with a history of severe peripheral arteritis and transient ischemic cardiovascular accident (pretherapy MIC penicillin < 0.016 mg/L; amoxicillin < 0.016 mg/L); one patient with chronic bronchitis, hypertension and chronic respiratory/cardiac failure (0.16 mg/L, 0.16 mg/L), and three patients with no significant medical history (0.25 mg/L: 0.5 mg/L, < 0.023 mg/L: < 0.016 mg/L, 0.032 mg/L, < 0.016 mg/L, respectively).

Safety

Adverse events considered by the investigator to be related (possible or probable) to the study medication were recorded during therapy in 56 of 200 patients (28%) evaluable for safety in the moxifloxacin group and 42 of 208 patients (20.2%) in the amoxicillin group. The most frequently recorded adverse events were GI disturbances in the moxifloxacin group, and liver function test abnormalities, increased γ-glutamyl transaminase (GGT), and diarrhea in the amoxicillin group (Table 9). No cases of photosensitivity or cardiac arrhythmias, particularly of ventricular origin, were reported in either treatment group during study medication. Drug-related adverse events in both treatment group were mainly mild to moderate in intensity and were resolved. Severe drug-related adverse events were experienced by five patients. One patient in the moxifloxacin treatment group experienced dizziness and four patients in the amoxicillin treatment group experienced six adverse events: pneumonia (n = 2), atrial fibrillation (n = 1), and arrhythmia, agitation, and acute kidney failure (n = 1 each).

Serious adverse events were reported in 23 patients in the moxifloxacin group and 19 patients in the amoxicillin group. The majority of serious adverse events in both treatment arms were related to the respiratory or cardiovascular system. Twelve serious adverse events were thought to be probably or possibly related to the study drug: pneumonia in two patients in the moxifloxacin group and 10 events in seven patients in the amoxicillin group: liver function test abnormalities (n = 3), rash (n = 1), acute kidney failure and agitation (n = 1), convulsion (n = 1), and pneumonia (n = 1). All serious drug-related events resolved except acute kidney failure (worsened) and agitation (improved).

Sixteen patients discontinued study medication due to an adverse event. Eight patients in the moxifloxacin group discontinued medication due to rash and diarrhea; enlarged abdomen and allergic reaction; leg pain; uremia; rash; pneumonia (n = 3). Eight patients in the amoxicillin group discontinued medication due to leukopenia and thrombocytopenia; apnea; pneumonia (n = 2); convulsions; abnormal liver function and increased GGT; allergic reaction; rash, eosinophilia, and increased GGT.

Seven patients (three in the moxifloxacin group and four in the amoxicillin group) died during the study. In the moxifloxacin group, one patient with a history of cor pulmonale and chronic bronchitis died from cor pulmonale, thrombus in the left ventricle, and pulmonary edema on day 10 of study medication; one patient with a history of hypertension died from a cerebrovascular accident 33 days after the end of study medication; and one patient with a history of atrial fibrillation and cardiac failure died from ventricular fibrillation 52 days after the end of study medication. In the amoxicillin group, one patient with a history of diabetes mellitus, hypertension, and ischemic cardiopathy died 1 day after the last intake of study medication from probable pulmonary embolism, one patient died 9 days after the last intake of study medication also of probable pulmonary embolism, one patient with a history of alcoholism and COPD died from cardiorespiratory failure on the first day after last intake of study medication, and one patient with acute renal failure and neurologic disturbances died from cardiac arrhythmia after intubation in the ICU 3 days after the EOT. None of the deaths were considered to be related to study drug treatment.

No treatment-related differences were detected in the analysis of vital signs, and no major differences were detected in the analyses of laboratory parameters between the treatment groups.

Despite recent, significant advances in drug therapy and medical technology that have had great impact on the course of many diseases, CAP continues to present a challenge to clinicians. One of the principal reasons for this is the wide and increasing range of causative pathogens and their changing patterns of susceptibility to available antibacterial agents. Of particular concern is the increasing prevalence of penicillin and macrolide resistance in strains of S pneumoniae. The majority of pneumococci responsible for mild to moderate CAP respond to treatment with penicillin or amoxicillin, although higher dosages are required.2628 The French Consensus Conference in 1991 recommended the use of amoxicillin, 1,000 mg tid, which was later validated.5,2930 However, increasing the dose of penicillin is likely only to be a temporary approach, as increasing resistance to penicillin is only part of the problem. The prevalence of resistance to other traditionally used antibiotics, such as erythromycin, tetracycline, and trimethoprim-sulfamethoxazole is much greater in penicillin-resistant strains of S pneumoniae than in penicillin susceptible strains. Newer macrolides such as azithromycin or clarithromycin also appear to be ineffective against penicillin-resistant pneumococci. Since penicillin resistance results from alterations in penicillin-binding proteins, the activity of aminopenicillins, cephalosporins, and carbapenems against penicillin-resistant strains of pneumococci is also diminished.

The trend toward increasing resistance patterns worldwide for most community-acquired respiratory pathogens necessitates the search for new antimicrobial agents that can be confidently administered empirically. The number of therapeutic options available to clinicians has been broadened by the recent development of fluoroquinolones with enhanced activity against S pneumoniae. Earlier compounds, such as ciprofloxacin and ofloxacin, were not regarded as first-choice agents in cases of documented pneumococcal pneumonia. The new fluoroquinolones possess activity against S pneumoniae that is consistently good and unaffected by penicillin or macrolide resistance.31 Clinically, the question to be answered is whether these agents will work, particularly if administered orally. Several clinical trials3137 have established clear-cut evidence of fluoroquinolone activity in comparison to that of other antimicrobial agents (amoxicillin, amoxicillin/clavulanic acid, erythromycin, cefaclor) in the treatment of CAP. The majority of patients in these studies, whether treated in or out of hospital, had mild-to-moderate disease. Only one study32 was designed specifically to examine the efficacy of new fluoroquinolones in the treatment of pneumococcal pneumonia.

The present study was designed to assess the efficacy and safety of moxifloxacin at a dose of 400 mg/d for 10 days in comparison to the“ gold standard” β-lactam antibiotic, amoxicillin, at a dose of 1,000 mg tid, for 10 days for the treatment of adults with suspected pneumococcal CAP. Patients included in this study were a population with clinical and radiographic features corresponding to well-documented adult CAP. Ninety-one cases of proven pneumococcal pneumonia were available for efficacy analysis, including 33 cases with strains of S pneumoniae that were intermediately susceptible (n = 22) or highly resistant (n = 11) to penicillin. Pneumonia treated in this study was mild to moderate, as confirmed by the low number of patients with infiltrate involving more than one lobe at baseline chest radiograph, and the low mortality observed during the study.

For the primary efficacy parameter of clinical response after 3 to 5 days of therapy in the evaluable population, moxifloxacin therapy was demonstrated to be at least as effective as amoxicillin therapy, with a clinical cure rate of 91% and 90%, respectively. The clinical success rate is comparable to that of published experiences.29 The total number of failures related to ineffective antibiotic therapy was 15 in the moxifloxacin group and 19 in the amoxicillin group. S pneumoniae was the causative agent in five cases of moxifloxacin therapy failure and seven cases of amoxicillin-therapy failure. Subgroup analyses of bacteriologically evaluable patients, particularly those with documented pneumococcal pneumonia, did not show any differences between treatment groups with respect to the clinical success rate. As with the clinical response, the bacteriologic success rate was similar in both arms. Furthermore, 43 of 48 patients (90%) treated with moxifloxacin and 39 of 46 patients (85%) treated with amoxicillin, from whom S pneumoniae was isolated from either respiratory or blood cultures at baseline, were considered as bacteriologic successes at the EOT. Bacteriologic response to S pneumoniae was independent of the results of pretherapy penicillin susceptibility testing, in both treatment groups.

In selecting an antimicrobial agent for the treatment of CAP, the practitioner must not only consider efficacy, but also the safety profile of the agent. In this trial, both study drugs were well tolerated, with the number of drug-related adverse events being comparable. Phototoxic reactions have been reported for several quinolones, but in this study, no cases of photosensitivity were reported in the moxifloxacin group.38A large number of drugs from different classes, including some antibacterials, are known to prolong the ECG QT interval, one of the risk factors in the development of torsades de pointes.39The potential of quinolones agents, notably sparfloxacin and grepafloxacin, to induce QT prolongation has been recognized.4041 In the present study, ventricular tachycardia or torsade de pointes were not observed during study drug therapy in either treatment group. The rate of premature termination of study drug therapy due to adverse events was similar in both treatment groups (eight patients in each arm). None of the seven deaths (three in the moxifloxacin group and four in the amoxicillin group) that occurred during the study were related to study medication.

In conclusion, this study demonstrated that moxifloxacin given as a single daily 400-mg oral dose for 10 days is an effective and well-tolerated treatment for adult patients with mild-to-moderate suspected pneumococcal CAP and was equivalent to the standard treatment of high-dose amoxicillin three times daily. However, with the increasing prevalence of high-level penicillin resistance among clinical isolates of S pneumoniae around the world, the amoxicillin regimen may not remain an option. The activity of the newer fluoroquinolones seems to be unaffected by penicillin or macrolide resistance, and thus moxifloxacin is likely to offer clinicians a reliable option in the face of increasing antibiotic resistance. Its once-daily dosing regimen, which may enhance patient compliance, also supports its use as outpatient therapy for patients with CAP.

Members of the CAP5 Moxifloxacin Study Group are as follows:

Argentina: Dr. Jasovich (Bueno Aires). Brazil: Dr. De Brito Jardim (Sao Paulo). Chile: Dr. Wolff (Santiago). Croatia: Dr. Gasparovic (Zagreb). Czech Republic: Dr. Baresova (Prague), Dr. Dosedel (Prague), Dr. Fabian (Prague), Dr. Marel (Prague), Dr. Sedlak (Prague), Dr. Sellenberg (Prague). Estonia: Dr. Toim (Tallinn). France: Professor Baron (Nantes), Dr. Bernabeu (Chauny), Dr. Boudoux (Armentières), Professor Carles (Toulouse), Dr. Chaumier (Aubergenville), Professor Clavier (Brest), Dr. Deborne (Nanterre), Dr. Dien (Saint Brieuc), Dr. Elkharat (Paris), Dr. Froment (Bar le Duc), Dr. Grignet (Denain), Dr. Guelaud (Aubergenville), Dr. Herengt (Arras), Dr. Korach (Chalons sur Marne), Dr. Le Chevalier (Caen), Dr. Leclerc (Saint Germain en Laye), Dr. Le Groumellec (Vannes), Professor Leophonte (Toulouse), Dr. Mathieu (Aulnay sous Bois), Dr. Meeus (Saint Germain en Laye), Professor Nouvet (Rouen), Professor Pariente (Clichy), Professor Patte (Poitiers), Dr. Proust (Nïmes), Dr. Prud’homme (Tarbes), Dr. Ruyer (Belfort), Professor Tuchais (Angers), Dr. Vanche (Auch), Dr. Veyssier (Compiègne), Dr. Vives (Saint Gaudens), Dr. Wagschal (Vesoul). Hong-Kong: Dr. Chiu, Dr. Kam. Hungary: Dr. Ludwig (Budapest), Dr. Nagy (Budapest), Dr. Princz (Budapest), Dr. Strausz (Budapest), Dr. Szilasi (Debrecen), Dr. Timar (Kecskemet). Lithuania: Dr. Norvaisas (Klaipeda), Professor Venalis (Vilnius). Mexico: Dr. Aguilera (Mexico), Dr. Alva Y Perez (Ciuadad Juarez), Dr. Estrada (Mexico), Dr. Loera (Durango), Dr. Morales (Jalisco), Dr. Obispo (Tijuana), Dr. Rico (Mexico), Dr. Urueta (Mexico). Portugal: Dr. Banha (Setubal), Dr. Branco Pires (Coimbra), Dr. Wink (Porto). Russia: Professor Fedoseev (Saint Petersburg), Professor Jakovlev (Moscow), Professor Korovina (Saint Petersburg), Professor Sherstnev (Moscow), Professor Shilkin (Moscow), Professor Solomatin (Moscow), Professor Trofimov (Saint Petersburg). Slovenia: Dr. Muzlovic (Ljublana). South Africa: Dr. Ogundare (Boksburg), Dr. Tsitsi (Olifantsfontein). Spain: Dr. Morera (Badalona), Dr. Rodriguez (Las Palma de Gran Canaria), Dr. Torres (Barcelona), Dr. Valencia (Malaga). Turkey: Dr. Calangu (Istambul), Dr. Yuce (Izmir). United Kingdom: Dr. Cochrane (London), Dr. Honeybourne (Birmingham). Ukraine: Dr. Feshcenko (Kiev), Dr. Yashina (Kiev). Uruguay: Dr. Bagnulo (Montevideo).

Abbreviations: CAP = community-acquired pneumonia; EOT = end of therapy; GGT = γ-glutamyl transaminase; ITT = intent to treat; MIC = minimum inhibitory concentration; PP = per protocol

Dr. Petitprez has served as a lecturer and occasional consultant for the following pharmaceutical companies: Astra, Bayer, Glax

Wellcome, Roche, Rhone-Poulenc Rorer and SmithKline Beecham. Dr. Arvis is a Clinical Project Leader at Bayer Pharma, France. Dr. Marel has not been a consultant for any pharmaceutical companies. Dr. Moita has served as an occasional consultant with the following pharmaceutical companies: Astra, Novartis, Pfizer, Solvay and Upjohn. Dr. Urueta has been a consultant for the following: Bayer, ICN Grossman, and Pharmacia & Upjohn. Dr. Urueta holds no equity position in any of the entities above. Dr. Urueta has served as a lecturer for Bayer and Pharmacia & Upjohn.

Table Graphic Jump Location
Table 1. Distribution of Patients for Efficacy and Safety Analysis*
* 

Data are presented as No. (%).

Table Graphic Jump Location
Table 2. Summary of Demographic and Other Baseline Characteristics in Evaluable PP Patients*
* 

Data are presented as mean ± SD or % unless otherwise indicated.

Table Graphic Jump Location
Table 3. Bacteriologic Documentation of S pneumoniae Pneumonia in Evaluable Patients*
* 

Data are presented as No. of patients (%).

Table Graphic Jump Location
Table 4. Clinical Success Rates the EOT and Follow-up in the ITT and Evaluable Patients*
* 

Data are presented as No. of patients (%) unless otherwise indicated. CI = confidence interval.

 

Nonclinical success at the EOT carried forward.

Table Graphic Jump Location
Table 5. Clinical Response in Evaluable Patients With Proven Pneumococcal Pneumonia at the EOT and Follow-up*
* 

Data are presented as No. of patients (%).

 

Clinical failures at end of therapy carried forward.

Table Graphic Jump Location
Table 6. Clinical Response in Evaluable Patients With Pneumococcal Pneumonia According to Baseline Penicillin Susceptibility Testing, at the EOT and Follow-up*
* 

Data are presented as No. of patients (%).

 

Pen S (penicillin sensitive): MIC < 0.1 mg/L.

 

Pen I (intermediately penicillin susceptible): MIC 0.1 to 1.0 mg/L.

§ 

Pen R (highly penicillin resistant): MIC > 1.0 mg/L.

 

Clinical failures at EOT carried forward.

Table Graphic Jump Location
Table 7. Bacteriologic Response in Evaluable Patients at the EOT and Follow-up*
* 

Data are presented as No. of patients (%).

 

Eradication or presumed eradication.

 

Persistence, presumed persistence, or persistence with superinfection.

§ 

Any bacteriologic failure at the EOT is counted.

 

Persistence, presumed persistence, persistence with superinfection, or reinfection.

Table Graphic Jump Location
Table 8. Bacteriologic Success Rate (Eradication or Presumed Eradication) at the EOT for the Most Frequently Isolated Baseline Pathogens*
* 

Data are presented as No. of patients (%).

Table Graphic Jump Location
Table 9. Possible or Probable Study Drug-Related Adverse Events Most Frequently Reported During Treatment*
* 

Data are presented as No. of patients (%).

We would like to thank J. Felmingham and B. Robertson for help in preparation of the article.

Macfarlane, J (1994) An overview of community-acquired pneumonia with lessons learned from the British Thoracic Society study.Semin Respir Infect9,153-165. [PubMed]
 
Marrie, TJ Community-acquired pneumonia.Clin Infect Dis1994;18,501-505. [PubMed]
 
Niederman, MS, Bass, J, Campbell, GD, et al Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity and initial antimicrobial therapy.Am Rev Respir Dis1993;148,1418-1426. [PubMed]
 
British Thoracic Society.. Guidelines for the management of community-acquired pneumonia in adults admitted to hospital.Br J Hosp Med1993;49,349-350
 
Quatrième Conférence de Consensus en Thérapeutique Anti-infectieuse, Lille, 18 Octobre 1991. Les infections des voies respiratoires. Quatrième Conférence de Consensus en Thérapeutique Anti-infectieuse de la société de Pathologie Infectieuse de Langue Française, Lille, 1991. Med Mal Infect 1992; 22, No. Special (Février).
 
Mandell, LA, Niederman, M The Canadian community-acquired pneumonia consensus conference group.Can J Infect Dis1993;4,25-28. [PubMed]
 
Austrian, R Confronting drug-resistant pneumococci.Ann Intern Med1994;121,807-809. [PubMed]
 
Appelbaum, PC Antimicrobial resistance inStreptococcus pneumoniae: an overview.Clin Infect Dis1992;15,77-83. [CrossRef] [PubMed]
 
Linares, J, Tubau, FE, Alcaide, F, et al Antimicrobial resistance ofS pneumoniae: comparison of thein vitroactivity of 16 antibiotics.Curr Ther Res1996;57(suppl A),57-64
 
Yee, YC, Thornsberry, C Penicillin-resistantS. pneumoniaeon the rise in the United States: its effects on oral cephalosporins.Antimicrob Infect Dis Newslett1994;13,49-57. [CrossRef]
 
Goldstein, FW, Acar, JF Antimicrobial resistance among lower respiratory tract isolates ofStreptococcus pneumoniae: results of a 1992–93 western Europe and USA collaborative surveillance study; The Alexander Project Collaborative Group.J Antimicrob Chemother1996;38(suppl A),71-84. [PubMed]
 
for the French Study Group. Péan, Y, Goldstein, FW, Guerrier, MC Highlights of the French antimicrobial resistance surveillance project.Diagn Microbiol Infect Dis1996;25,191-194. [CrossRef] [PubMed]
 
Frieden, TR, Mangi, RJ Inappropriate use of oral ciprofloxacin.JAMA1990;264,1438-1440. [CrossRef] [PubMed]
 
Weiss, K, Laverdiere, M, Restieri, C Comparative activity of trovafloxacin and BAY 12–8039 against 452 clinical isolates ofStreptococcus pneumoniae.J Antimicrob Chemother1998;42,523-525. [CrossRef] [PubMed]
 
Biedenbach, DJ, Barrett, MS, Croco, MAT, et al BAY 12–8039, a novel fluoroquinolone activity against important respiratory tract pathogens.Diagn Microbiol Infect Dis1998;31,45-50
 
Schmidt H, Dalhoff A, Stuertz K, et al. Moxifloxacin in the therapy of experimental pneumococcal meningitis. Antimicrob Agents Chemother 1998; 42:6:1397–1401.
 
Bébéar CM, Renaudin H, Boudjadja A, et al.In vitro activity of BAY 12–8039, a new fluoroquinolone, against mycoplasmas. Antimicrob Agents Chemother 1998; 42:3:703–704.
 
Roblin PM, Hammerschlag MR.In vitroactivity of a new 8-methoxyquinolone, BAY 12–8039, againstChlamydia pneumoniae. Antimicrob Agents Chemother 1998; 42:4:951–952
 
Ruckdeschel, G, Dalhoff, A In vitroactivity of moxifloxacin against Legionella species and the effect of medium on susceptibility test results.J Antimicrob Chemother1999;43,25-29
 
Sullivan JT, Woodruff M, Lettieri J, et al. Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12–8039), a new enantiomerically pure 8-methoxyquinolone. Antimicrob Agents Chemother 1999; 43:11:2793–2797.
 
Wise, R A review of the clinical pharmacology of moxifloxacin, a new 8-methoxyquinolone, and its potential relation to therapeutic efficacy.Clin Drug Invest1999;17,365-387. [CrossRef]
 
Blondeau, JM, Felmingham, D In vitroandin vivoactivity of moxifloxacin against community respiratory tract pathogens.Clin Drug Invest1999;18,57-78. [CrossRef]
 
Soman, A, Honeybourne, D, Andrews, J, et al Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fiber-optic bronchoscopy.J Antimicrob Chemother1999;44,835-838. [CrossRef] [PubMed]
 
Bartlett, JG, Breiman, RF, Mandell, LA, et al Guidelines from the Infectious Diseases Society of America: community-acquired pneumonia in adults; guidelines for management.Clin Infect Dis1998;26,811-838. [CrossRef] [PubMed]
 
Bohte, R, Hermans, J, van den Broek, PJ Early recognition ofStreptococcus pneumoniaein patients with community-acquired pneumonia.Eur J Clin Microbiol Infect Dis1996;15,201-205. [CrossRef] [PubMed]
 
Carbon C, Leophonte P, Petitpretz P, et al. Efficacy and safety of temafloxacin versus those of amoxicillin in hospitalized adults with community-acquired pneumonia. Antimicrob Agents Chemother 1992; 36:4:833–839.
 
Goldstein, F, Garau, J Resistant pneumococci: a new threat in respiratory infections.Scand J Infect Dis1994;93,55-62
 
Capauto, GM, Applebaum, PC, Liu, HH Infections due to penicillin-resistant pneumococci: clinical, epidemiologic and microbiologic features.Arch Intern Med1993;153,1301-1310. [CrossRef] [PubMed]
 
Carbon, C, Leophonte, P Recommendations posologiques concernant l’amoxicilline et l’amoxicilline-acide clavulanique dans les pneumopathies communautaires de l’adulte à l’hôpital.Med Mal Infect1997;27(spécial),73-78
 
Bedos, JP, Moine, P Modèles expérimentaux d’infections àStreptococcus pneumoniaede sensibilité diminuée à la pénicilline G: analyze critique de l’activité de l’amoxicillin.Med Mal Infect1997;27(spécial),79-85
 
File TM, Segreti J, Dunbar L, et al. A multicentre randomised study comparing the efficacy and safety on intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in the treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997; 41:9:1965–1972.
 
Aubier, M, Verster, R, Regamey, C, et al Once-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired, suspected pneumococcal pneumonia in adults.Clin Infect Dis1998;26,1312-1320. [CrossRef] [PubMed]
 
Lode, H, Garau, J, Grassi, C, et al Treatment of community-acquired pneumonia: a randomised comparison of sparfloxacin, amoxycillin-clavulanic acid and erythromycin.Eur Respir J1995;8,1999-2007. [CrossRef] [PubMed]
 
O’deherty B, Dutchman DA, Pettit R, et al. A randomised double-blind, comparative study of grepafloxacin and amoxicillin in the treatment of patients with community-acquired pneumonia. J Antimicrob Chemother 1997; 40(Suppl A):73–81.
 
Ortquist A, Valtonen M, Cars O, et al. Oral empiric treatment of community-acquired pneumonia: a multicenter double-blind, randomized study comparing sparfloxacin with roxithromycin. Chest 1996; 110:6:1499–1506.
 
Donovitz GR, Brandon ML, Salisbury JP, et al. Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia; a randomised, double-masked, comparative, multicentre study. Clin Ther 1997; 19:5:936–953.
 
Trémolières, F, de Kock, F, Pluck, N, et al Trovafloxacin versus high-dose amoxicillin (1 g three times daily) in the treatment of community-acquired bacterial pneumonia.Eur J Clin Microbiol Infect Dis1998;17,447-453. [PubMed]
 
Ferguson, J Fluoroquinolones photosensitization: a review of clinical and laboratory studies.Photochem Photobiol1995;62,954-958
 
Benedict, CR The QT interval and drug associated torsades de pointes.Drug Invest1993;5,69-79
 
Jaillon, P, Morganroth, J, Brumpt, I, et al Overview of electrocardiographic and cardiovascular safety data for sparfloxacin.J Antimicrob Chemother1996;37(Suppl A),161-167. [PubMed]
 
Stahlmann, R, Schwabe, R Safety profile of grepafloxacin compared with other fluoroquinolones.J Antimicrob Chemother1997;40(Suppl A),83-92. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Distribution of Patients for Efficacy and Safety Analysis*
* 

Data are presented as No. (%).

Table Graphic Jump Location
Table 2. Summary of Demographic and Other Baseline Characteristics in Evaluable PP Patients*
* 

Data are presented as mean ± SD or % unless otherwise indicated.

Table Graphic Jump Location
Table 3. Bacteriologic Documentation of S pneumoniae Pneumonia in Evaluable Patients*
* 

Data are presented as No. of patients (%).

Table Graphic Jump Location
Table 4. Clinical Success Rates the EOT and Follow-up in the ITT and Evaluable Patients*
* 

Data are presented as No. of patients (%) unless otherwise indicated. CI = confidence interval.

 

Nonclinical success at the EOT carried forward.

Table Graphic Jump Location
Table 5. Clinical Response in Evaluable Patients With Proven Pneumococcal Pneumonia at the EOT and Follow-up*
* 

Data are presented as No. of patients (%).

 

Clinical failures at end of therapy carried forward.

Table Graphic Jump Location
Table 6. Clinical Response in Evaluable Patients With Pneumococcal Pneumonia According to Baseline Penicillin Susceptibility Testing, at the EOT and Follow-up*
* 

Data are presented as No. of patients (%).

 

Pen S (penicillin sensitive): MIC < 0.1 mg/L.

 

Pen I (intermediately penicillin susceptible): MIC 0.1 to 1.0 mg/L.

§ 

Pen R (highly penicillin resistant): MIC > 1.0 mg/L.

 

Clinical failures at EOT carried forward.

Table Graphic Jump Location
Table 7. Bacteriologic Response in Evaluable Patients at the EOT and Follow-up*
* 

Data are presented as No. of patients (%).

 

Eradication or presumed eradication.

 

Persistence, presumed persistence, or persistence with superinfection.

§ 

Any bacteriologic failure at the EOT is counted.

 

Persistence, presumed persistence, persistence with superinfection, or reinfection.

Table Graphic Jump Location
Table 8. Bacteriologic Success Rate (Eradication or Presumed Eradication) at the EOT for the Most Frequently Isolated Baseline Pathogens*
* 

Data are presented as No. of patients (%).

Table Graphic Jump Location
Table 9. Possible or Probable Study Drug-Related Adverse Events Most Frequently Reported During Treatment*
* 

Data are presented as No. of patients (%).

References

Macfarlane, J (1994) An overview of community-acquired pneumonia with lessons learned from the British Thoracic Society study.Semin Respir Infect9,153-165. [PubMed]
 
Marrie, TJ Community-acquired pneumonia.Clin Infect Dis1994;18,501-505. [PubMed]
 
Niederman, MS, Bass, J, Campbell, GD, et al Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity and initial antimicrobial therapy.Am Rev Respir Dis1993;148,1418-1426. [PubMed]
 
British Thoracic Society.. Guidelines for the management of community-acquired pneumonia in adults admitted to hospital.Br J Hosp Med1993;49,349-350
 
Quatrième Conférence de Consensus en Thérapeutique Anti-infectieuse, Lille, 18 Octobre 1991. Les infections des voies respiratoires. Quatrième Conférence de Consensus en Thérapeutique Anti-infectieuse de la société de Pathologie Infectieuse de Langue Française, Lille, 1991. Med Mal Infect 1992; 22, No. Special (Février).
 
Mandell, LA, Niederman, M The Canadian community-acquired pneumonia consensus conference group.Can J Infect Dis1993;4,25-28. [PubMed]
 
Austrian, R Confronting drug-resistant pneumococci.Ann Intern Med1994;121,807-809. [PubMed]
 
Appelbaum, PC Antimicrobial resistance inStreptococcus pneumoniae: an overview.Clin Infect Dis1992;15,77-83. [CrossRef] [PubMed]
 
Linares, J, Tubau, FE, Alcaide, F, et al Antimicrobial resistance ofS pneumoniae: comparison of thein vitroactivity of 16 antibiotics.Curr Ther Res1996;57(suppl A),57-64
 
Yee, YC, Thornsberry, C Penicillin-resistantS. pneumoniaeon the rise in the United States: its effects on oral cephalosporins.Antimicrob Infect Dis Newslett1994;13,49-57. [CrossRef]
 
Goldstein, FW, Acar, JF Antimicrobial resistance among lower respiratory tract isolates ofStreptococcus pneumoniae: results of a 1992–93 western Europe and USA collaborative surveillance study; The Alexander Project Collaborative Group.J Antimicrob Chemother1996;38(suppl A),71-84. [PubMed]
 
for the French Study Group. Péan, Y, Goldstein, FW, Guerrier, MC Highlights of the French antimicrobial resistance surveillance project.Diagn Microbiol Infect Dis1996;25,191-194. [CrossRef] [PubMed]
 
Frieden, TR, Mangi, RJ Inappropriate use of oral ciprofloxacin.JAMA1990;264,1438-1440. [CrossRef] [PubMed]
 
Weiss, K, Laverdiere, M, Restieri, C Comparative activity of trovafloxacin and BAY 12–8039 against 452 clinical isolates ofStreptococcus pneumoniae.J Antimicrob Chemother1998;42,523-525. [CrossRef] [PubMed]
 
Biedenbach, DJ, Barrett, MS, Croco, MAT, et al BAY 12–8039, a novel fluoroquinolone activity against important respiratory tract pathogens.Diagn Microbiol Infect Dis1998;31,45-50
 
Schmidt H, Dalhoff A, Stuertz K, et al. Moxifloxacin in the therapy of experimental pneumococcal meningitis. Antimicrob Agents Chemother 1998; 42:6:1397–1401.
 
Bébéar CM, Renaudin H, Boudjadja A, et al.In vitro activity of BAY 12–8039, a new fluoroquinolone, against mycoplasmas. Antimicrob Agents Chemother 1998; 42:3:703–704.
 
Roblin PM, Hammerschlag MR.In vitroactivity of a new 8-methoxyquinolone, BAY 12–8039, againstChlamydia pneumoniae. Antimicrob Agents Chemother 1998; 42:4:951–952
 
Ruckdeschel, G, Dalhoff, A In vitroactivity of moxifloxacin against Legionella species and the effect of medium on susceptibility test results.J Antimicrob Chemother1999;43,25-29
 
Sullivan JT, Woodruff M, Lettieri J, et al. Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12–8039), a new enantiomerically pure 8-methoxyquinolone. Antimicrob Agents Chemother 1999; 43:11:2793–2797.
 
Wise, R A review of the clinical pharmacology of moxifloxacin, a new 8-methoxyquinolone, and its potential relation to therapeutic efficacy.Clin Drug Invest1999;17,365-387. [CrossRef]
 
Blondeau, JM, Felmingham, D In vitroandin vivoactivity of moxifloxacin against community respiratory tract pathogens.Clin Drug Invest1999;18,57-78. [CrossRef]
 
Soman, A, Honeybourne, D, Andrews, J, et al Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fiber-optic bronchoscopy.J Antimicrob Chemother1999;44,835-838. [CrossRef] [PubMed]
 
Bartlett, JG, Breiman, RF, Mandell, LA, et al Guidelines from the Infectious Diseases Society of America: community-acquired pneumonia in adults; guidelines for management.Clin Infect Dis1998;26,811-838. [CrossRef] [PubMed]
 
Bohte, R, Hermans, J, van den Broek, PJ Early recognition ofStreptococcus pneumoniaein patients with community-acquired pneumonia.Eur J Clin Microbiol Infect Dis1996;15,201-205. [CrossRef] [PubMed]
 
Carbon C, Leophonte P, Petitpretz P, et al. Efficacy and safety of temafloxacin versus those of amoxicillin in hospitalized adults with community-acquired pneumonia. Antimicrob Agents Chemother 1992; 36:4:833–839.
 
Goldstein, F, Garau, J Resistant pneumococci: a new threat in respiratory infections.Scand J Infect Dis1994;93,55-62
 
Capauto, GM, Applebaum, PC, Liu, HH Infections due to penicillin-resistant pneumococci: clinical, epidemiologic and microbiologic features.Arch Intern Med1993;153,1301-1310. [CrossRef] [PubMed]
 
Carbon, C, Leophonte, P Recommendations posologiques concernant l’amoxicilline et l’amoxicilline-acide clavulanique dans les pneumopathies communautaires de l’adulte à l’hôpital.Med Mal Infect1997;27(spécial),73-78
 
Bedos, JP, Moine, P Modèles expérimentaux d’infections àStreptococcus pneumoniaede sensibilité diminuée à la pénicilline G: analyze critique de l’activité de l’amoxicillin.Med Mal Infect1997;27(spécial),79-85
 
File TM, Segreti J, Dunbar L, et al. A multicentre randomised study comparing the efficacy and safety on intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in the treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997; 41:9:1965–1972.
 
Aubier, M, Verster, R, Regamey, C, et al Once-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired, suspected pneumococcal pneumonia in adults.Clin Infect Dis1998;26,1312-1320. [CrossRef] [PubMed]
 
Lode, H, Garau, J, Grassi, C, et al Treatment of community-acquired pneumonia: a randomised comparison of sparfloxacin, amoxycillin-clavulanic acid and erythromycin.Eur Respir J1995;8,1999-2007. [CrossRef] [PubMed]
 
O’deherty B, Dutchman DA, Pettit R, et al. A randomised double-blind, comparative study of grepafloxacin and amoxicillin in the treatment of patients with community-acquired pneumonia. J Antimicrob Chemother 1997; 40(Suppl A):73–81.
 
Ortquist A, Valtonen M, Cars O, et al. Oral empiric treatment of community-acquired pneumonia: a multicenter double-blind, randomized study comparing sparfloxacin with roxithromycin. Chest 1996; 110:6:1499–1506.
 
Donovitz GR, Brandon ML, Salisbury JP, et al. Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia; a randomised, double-masked, comparative, multicentre study. Clin Ther 1997; 19:5:936–953.
 
Trémolières, F, de Kock, F, Pluck, N, et al Trovafloxacin versus high-dose amoxicillin (1 g three times daily) in the treatment of community-acquired bacterial pneumonia.Eur J Clin Microbiol Infect Dis1998;17,447-453. [PubMed]
 
Ferguson, J Fluoroquinolones photosensitization: a review of clinical and laboratory studies.Photochem Photobiol1995;62,954-958
 
Benedict, CR The QT interval and drug associated torsades de pointes.Drug Invest1993;5,69-79
 
Jaillon, P, Morganroth, J, Brumpt, I, et al Overview of electrocardiographic and cardiovascular safety data for sparfloxacin.J Antimicrob Chemother1996;37(Suppl A),161-167. [PubMed]
 
Stahlmann, R, Schwabe, R Safety profile of grepafloxacin compared with other fluoroquinolones.J Antimicrob Chemother1997;40(Suppl A),83-92. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543