The efficacy and safety of two oral moxifloxacin regimens compared to oral clarithromycin in the treatment of community-acquired pneumonia.

An international multi-centre, randomized, prospective, double-blind study compared oral moxifloxacin (200 mg or 400 mg once daily for 10 days) with oral clarithromycin (500 mg, twice daily for 10 days) in the treatment of community-acquired pneumonia (CAP). The clinical success rate in the evaluable population at the primary efficacy assessment, 3-5 days after the end of study treatment, was 93.9% in patients treated with 200 mg moxifloxacin; 94.4%, with 400 mg moxifloxacin; and 94.3%, with clarithromycin. Clinical success rates were maintained at follow-up, 21-28 days after the end of treatment: 90.7% (200 mg moxifloxacin), 92.8% (400 mg moxifloxacin) and 92.2% (clarithromycin). The 95% confidence intervals indicated that all three treatment regimens were equally effective in treating CAP. At follow-up, the 400 mg moxifloxacin dose had a slightly higher observed cure rate than the 200 mg moxifloxacin dose, but this was not statistically significant. The most frequently isolated pathogens were Streptococcus pneumoniae (42%), Haemophilus influenzae (19%), Haemophilus parainfluenzae (10%), Moraxella catarrhalis (6%), Klebsiella pneumoniae (5%) and Staphylococcus aureus (4%). The bacteriological success rate (eradication and presumed eradication) was 72.5% (29/40) for 200 mg moxifloxacin, 78.7% (37/47) for 400 mg moxifloxacin and 70.7% (29/41) for clarithromycin. The adverse event profile was comparable between the three treatment groups. Most adverse events, possibly or probably related to the study drug, were generally mild or moderate in severity and mostly related to the digestive system: diarrhoea, nausea and abdominal pain in 200 mg moxifloxacin patients; diarrhoea, liver function abnormalities and nausea in 400 mg moxifloxacin patients and liver function abnormalities, diarrhoea, nausea and taste perversion in clarithromycin patients. Study drugs were discontinued because of adverse events in 7/229 (3%) patients treated with 200 mg moxifloxacin, 11/224 (5%) with moxifloxacin 400 mg and 11/222 (5%) with clarithromycin. In all assessments, moxifloxacin was at least as effective clinically, and as well tolerated as clarithromycin in the treatment of CAP. Bacteriological success rates in moxifloxacin-treated patients were greater than those of clarithromycin. Moxifloxacin, given once daily, is free of many drug-drug interactions and requires no dosage adjustments in most renal hepatic deficient patients.     

Efficacy and safety of ten day moxifloxacin 400 mg once daily in the treatment of patients with community-acquired pneumonia. Community Acquired Pneumonia Study Group

Community-acquired pneumonia (CAP) remains a common and serious illness with approximately 2-4 million cases reported annually. Management of CAP is therapeutically challenging due to the increasing prevalence of penicillin- and macrolide-resistant pneumococci and beta-lactamase producing Haemophilus influenzae, as well as the increased recognition of 'atypical' pathogens, such as Chlamydia pneumoniae and Mycoplasma pneumoniae, and the frequent need for empiric therapy. We aimed to evaluate the safety and efficacy of moxifloxacin in the treatment of patients with CAP. To do this we carried out a prospective, uncontrolled, non-blind, Phase III clinical trial, in 27 U.S. centers. Patients included in the study were over 18 years of age with signs and symptoms of CAP confirmed by evidence of a new or progressive infiltrate on chest radiograph. The intervention used was moxifloxacin 400 mg PO once daily for 10 days. Sputum samples were collected pretherapy for Gram stain and culture for typical organisms. Culture and serological testing for Chlamydia pneumoniae and Mycoplasma pneumoniae was also performed. Susceptibility to moxifloxacin was determined by disk diffusion and MIC. Clinical and bacteriological responses were determined at the end of therapy (0-6 days post-therapy), follow-up (14-35 days post-therapy) and overall (end of therapy plus follow-up). Analyses were performed on both valid for efficacy and intent-to-treat populations. The primary efficacy variable was overall clinical resolution. Of 254 patients enrolled in the Study, 196 patients were included in the efficacy analyses. The majority of patients were male (58%) and Caucasian (85%) with a mean age of 49 years (range: 18 to 85 years). Only 3% of patients were hospitalized pretherapy. The most common pretherapy organisms identified, by culture or serology, in the valid for efficacy population (i.e. 147 organisms among 116 patients), were: Chlamydia pneumoniae (n=63; 54%), Mycoplasma pneumoniae (n=29; 25%), Streptococcus pneumoniae (n=14; 12%) and Haemophilus influenzae (n=13; 10%). End of therapy, follow-up and overall clinical resolution rates for the valid for efficacy population were 94%, 93% and 93%, respectively. The 95% CI for the overall clinical resolution rate was 88.1%, 95.9%. The overall bacteriological response for patients diagnosed by culture or serological criteria, was 91% (95% CI=84%, 96%). For patients who only met serological criteria for infection, the overall bacteriological response was 94% (60/64). Bacterial response rates for the four most commonly isolated pathogens were: 89% (56/63) for C. pneumoniae, 93% (27/29) for M. pneumoniae, 93% (13/14) for S. pneumoniae and 85% (11/13) for H. influenzae. Drug-related adverse events were reported in 33% (85/254) of moxifloxacin-treated patients. Nausea (9%), diarrhea (6%) and dizziness (4%) were the most commonly reported adverse events. Atypical organisms were isolated in high frequency among patients with CAP. Moxifloxacin 400 mg once daily for 10 days was effective and well-tolerated in the treatment of these adult patients with CAP. Moxifloxacin offers an effective treatment alternative for CAP due to both typical and atypical bacterial pathogens.     

A randomized trial comparing the cardiac rhythm safety of moxifloxacin vs levofloxacin in elderly patients hospitalized with community-acquired pneumonia

CONTEXT: Antimicrobial cardiac safety is of particular concern during the treatment of community-acquired pneumonia (CAP) in elderly patients, due to the presence of comorbid conditions and the use of multiple medications that may individually or synergistically affect cardiac repolarization. STUDY OBJECTIVE: To assess the cardiac rhythm safety of moxifloxacin vs levofloxacin in elderly patients hospitalized with CAP. DESIGN AND SETTING: Prospective, randomized, double-blind trial conducted at 47 hospitals in the United States. PATIENTS: Subjects > or = 65 years old with clinical signs/symptoms of CAP requiring initial parenteral therapy, including those with comorbidities. The safety population included 394 patients: 51.3% male; 85.3% white; mean age, 77.8 years. Two-thirds of the patients were > 75 years old, and 74.1% had a history of cardiac disease. INTERVENTIONS: Patients received IV/oral moxifloxacin (400 mg qd) or IV/oral levofloxacin (500 mg qd) for 7 to 14 days. Safety evaluations included 72 h of digital continuous 12-lead Holter monitoring, 12-lead ECGs at baseline and at maximum serum concentration on day 3, and adverse events. MAIN OUTCOME MEASURES: The primary safety end point was a composite of ventricular arrhythmia events based on Holter monitoring. RESULTS: Holter monitor data were available for 387 patients (192 receiving moxifloxacin and 195 receiving levofloxacin). Sixteen moxifloxacin-treated patients (8.3%) and 10 levofloxacin-treated patients (5.1%) had a primary composite cardiac event (p = 0.29); most events were nonsustained ventricular tachycardia (VT) [14 patients receiving moxifloxacin, 7.3%; and 10 patients receiving levofloxacin, 5.1%]. One moxifloxacin-treated patient had sustained monomorphic VT (> 30 s), and one levofloxacin-treated patient had torsade de pointes. Mean +/- SD QTc (Fridericia formula) change on day 3 was + 6.4 +/- 23.2 ms for moxifloxacin and - 2.5 +/- 22.9 ms for levofloxacin (p = 0.04). No deaths clearly related to study drugs occurred during the observation period. CONCLUSIONS: IV/oral moxifloxacin, although known to cause QTc interval prolongation, has a comparable cardiac rhythm safety profile to IV/oral levofloxacin in high-risk elderly patients with CAP.     

Cost analyses of community-acquired pneumonia from the hospital perspective

STUDY OBJECTIVES: Community-acquired pneumonia (CAP) is a widespread disease with important implications for health-care systems worldwide. This study investigated direct costs, treatment patterns, and outcomes associated with two patient cohorts hospitalized with CAP. DESIGN: The study design was naturalistic, prospective, and open. PATIENTS: The study enrolled 580 patients. Two hundred sixty-one patients were treated initially with IV moxifloxacin (45%, cohort M); the remaining 319 patients received nonstandardized treatment (cohort S). SETTING: Twenty-two hospitals in Germany. RESULTS: Clinical success rates were similar between treatment groups (cohort M, 242 of 256 patients, 95%; cohort S, 286 of 312 patients, 92%; p = 0.208). Mean +/- SD length of hospital stay was 10.8 +/- 5.2 days, with cohort M having a significantly shorter hospital stay (10.0 +/- 4 days) compared to cohort S (11.5 +/- 6 days; p < 0.001). Median of all direct costs was dollar 1,333 (minimum, dollar 127; maximum, dollar 9,488), with direct costs of dollar 1,250 in cohort M (minimum, dollar 372; maximum, dollar 9,488) and dollar 1,409 in cohort S (minimum, dollar 127; maximum, dollar 9,366) per treated episode of CAP (p = 0.066). CONCLUSIONS: Major determinants of costs were length of hospital stay and ICU admission, whereas costs for staff and hotel were major contributors to direct costs. Initial antibiotic therapy with moxifloxacin resulted in similar clinical efficacy and direct costs compared to nonstandardized therapy; however, patients treated with moxifloxacin benefited with an earlier hospital discharge.     

Eradication of H. influenzae in AECB: A pooled analysis of moxifloxacin phase III trials compared with macrolide agents

Haemophilus influenzae is the most common bacterial pathogen associated with acute exacerbations of chronic bronchitis (AECB). This study determined the rate of bacterial eradication of H. influenzae during AECB treated with either macrolides or moxifloxacin. Adult AECB patients with H. influenzae were included in a pooled analysis of four double-blind, multicentre, randomised trials. Patients received either moxifloxacin (400 mg qd for 5-10 days) or macrolides (azithromycin 500 mg/250 mg qd for 5 days or clarithromycin 500 mg bid for 5-10 days). Bacterial eradication and clinical success were recorded at the test-of-cure visit (7-37 days post-therapy). Of 2555 patients in the intent-to-treat population, 910 were microbiologically valid and 292 (32%) had H. influenzae cultured at baseline. Bacterial eradication of H. influenzae was significantly higher with moxifloxacin vs. macrolide-treated patients (93.0% [133/143] vs. 73.2% [109/149], respectively, P = 0.001). Moxifloxacin also demonstrated higher eradication rates compared with azithromycin (96.8% vs. 84.6%, P = 0.019) and clarithromycin (90.1% vs. 64.2%, P = 0.001) analysed separately. Clinical success was 89.5% (128/143) for moxifloxacin vs. 85.2% (127/149) for the macrolide group (P = 0.278); similar results were found when moxifloxacin was compared individually with each macrolide. For patients with AECB due to H. influenzae, moxifloxacin provided superior bacterial eradication rates than macrolide therapy.     

Oral moxifloxacin vs high-dosage amoxicillin in the treatment of mild-to-moderate, community-acquired, suspected pneumococcal pneumonia in adults

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.     

Switch therapy in hospitalized patients with community-acquired pneumonia: Tigecycline vs. Levofloxacin

ABSTRACT: BACKGROUND: Switch therapy is a management approach combining early discontinuation of intravenous (IV) antibiotics, switch to oral antibiotics, and early hospital discharge. This analysis compares switch therapy using tigecycline versus levofloxacin in hospitalized patients with community-acquired pneumonia (CAP). METHODS: A prospective, randomized, double blind, phase 3 clinical trial; patients were randomized to IV tigecycline (100 mg, then 50 mg q12h) or IV levofloxacin (500 mg q24h). Objective criteria were used to define time to switch therapy; patients were switched to oral levofloxacin after [greater than or equal to]6 IV doses if criteria met. Switch therapy outcomes were assessed within the clinically evaluable (CE) population. RESULTS: In the CE population, 138 patients were treated with IV tigecycline and 156 were treated with IV levofloxacin. The proportion of the population that met switch therapy criteria was 67.4% (93/138) for tigecycline and 66.7% (104/156) for levofloxacin. The proportion that actually switched to oral therapy was 89.9% (124/138) for tigecycline and 87.8% (137/156) for levofloxacin. Median time to actual switch therapy was 5.0 days each for tigecycline and levofloxacin. Clinical cure rates for patients who switched were 96.8% for tigecycline and 95.6% for levofloxacin. Corresponding cure rates for those that met switch criteria were 95.7% for tigecycline and 92.3% for levofloxacin. CONCLUSIONS: Switch therapy outcomes in hospitalized patients with CAP receiving initial IV therapy with tigecycline are comparable to those of patients receiving initial IV therapy with levofloxacin. These data support the use of IV tigecycline in hospitalized patients with CAP when the switch therapy approach is considered. ClinicalTrials.gov Identifier NCT00081575.     

Clinical and bacteriologic efficacy of telithromycin in patients with bacteremic community-acquired pneumonia

This retrospective analysis was performed to determine the clinical and bacteriologic efficacy of the ketolide antibacterial telithromycin in patients with community-acquired pneumonia (CAP) with pneumococcal bacteremia. Patients 13 years old with radiologically confirmed CAP and a positive blood culture for Streptococcus pneumoniae at screening were analyzed from eight multicenter Phase III/IV clinical trials. In four open-label, non-comparative studies, patients received telithromycin 800 mg once daily for 7-10 days. In four randomized, controlled, double-blind, comparative studies, patients received telithromycin 800 mg once daily for 5-10 days or a comparator antimicrobial (amoxicillin 1000 mg three times daily, clarithromycin 500 mg twice daily, or trovafloxacin 200 mg once daily) for 7-10 days. In total, 118 patients (telithromycin, 94/1061 [8.9%]; comparator, 24/244 [9.8%]) had documented pneumococcal bacteremia. Those who were treated with telithromycin achieved a clinical cure rate of 90.2% (74/82, per-protocol population); S. pneumoniae was eradicated in 77/82 (93.9%) bacteremic patients who received telithromycin and 15/19 (78.9%) comparator-treated patients. Clinical cure was also observed among telithromycin-treated bacteremic patients who were infected with penicillin- or erythromycin-resistant strains of S. pneumoniae (5/7 and 8/10, respectively). In conclusion, telithromycin achieves high clinical and bacteriologic cure rates in CAP patients with pneumococcal bacteremia.     

A Randomized Study of Sequential Intravenous/Oral Moxifloxacin in Comparison to Sequential Intravenous Ceftriaxone/Oral Cefuroxime Axetil in Patients with Hospital-Acquired Pneumonia

Abstract Background: Empiric treatment of hospital-acquired pneumonia (HAP) should be focused on the suspected pathogens. We evaluated the efficacy and safety of moxifloxacin vs ceftriaxone in patients with HAP without risk of infections with Pseudomonas aeruginosa and other non-fermentative Gram-negative bacteria. Patients and Methods: We performed a prospective, randomized, non-blind, multicentric and multinational study to compare the efficacy and safety of moxifloxacin 400 mg IV once daily followed by oral moxifloxacin 400 mg once daily to ceftriaxone 2 g IV once daily followed by oral cefuroxime axetil 500 mg twice daily to treat mild-to-moderate HAP in adult patients requiring initial parenteral therapy. The primary efficacy variable was clinical response 7–10 days after the end of a 7–14-day treatment period, secondary endpoints included clinical and bacteriologic response at different intervals for up to 31 days after treatment. The trial was terminated prematurely due to slow patient recruitment. Results: A total of 161 subjects (87 men, 74 women) between 18 and 95 years of age were enrolled, 120 of whom were eligible for per protocol efficacy analyses (60 each in the moxifloxacin and the comparator groups). Clinical success rates were 87% for moxifloxacin and 83% for the comparator [95% CI (–9.77 to 15.96%)]. The results for secondary endpoints were comparable between groups. Both treatments were safe and well tolerated. Conclusion: Moxifloxacin IV/oral can be considered as a possible alternative for the antibiotic treatment of patients with mild-to-moderate nosocomial pneumonia without risk factors for highly resistant microorganisms.     

An economic evaluation of sequential i.v./po moxifloxacin therapy compared to i.v./po co-amoxiclav with or without clarithromycin in the treatment of community-acquired pneumonia

STUDY OBJECTIVE: To evaluate costs, clinical consequences, and cost-effectiveness from a German and French health-care system perspective of sequential i.v./po moxifloxacin monotherapy compared to co-amoxiclav with or without clarithromycin (AMC +/- CLA) in patients with community-acquired pneumonia (CAP) who required parenteral treatment. METHODS: Costs and consequences over 21 days were evaluated based on clinical cure rates 5 to 7 days after treatment and health resource use reported for the TARGET multinational, prospective, randomized, open-label trial. This trial compared sequential i.v./po monotherapy with moxifloxacin (400 mg qd) to i.v./po co-amoxiclav (1.2 g i.v./625 mg po tid) with or without clarithromycin (500 mg bid) for 7 to 14 days in hospitalized patients with CAP. Since no country-by-treatment interaction was found in spite of some country differences for length of hospital stays, resource data (antimicrobial treatment, hospitalization, and out-of-hospital care) from all centers were pooled and valued using German and French unit prices to estimate CAP-related cost to the German Sickness Funds and French public health-care sector, respectively. RESULTS: Compared to AMC +/- CLA, treatment with moxifloxacin resulted in 5.3% more patients achieving clinical cure 5 to 7 days after therapy (95% confidence interval [CI], 1.2 to 11.8%), increased speed of response (1 day sooner for median time to first return to apyrexia, p = 0.008), and a reduction in hospital stay by 0.81 days (95% CI, - 0.01 to 1.63) within the 21-day time frame. Treatment with moxifloxacin resulted in savings of 266 euro and 381 euro for Germany and France respectively, primarily due to the shorter length of hospital stay. Cost-effectiveness acceptability curves show moxifloxacin has a > or = 95% chance of being cost saving from French and German health-care perspectives, and higher probability of being cost-effective at acceptability thresholds up to 2,000 euro per additional patient cured. CONCLUSION: i.v./po monotherapy with moxifloxacin shows clinical benefits including increased speed of response and is cost-effective compared to i.v./po AMC +/- CLA in the treatment of CAP.     

Short-term and long-term outcomes of moxifloxacin compared to standard antibiotic treatment in acute exacerbations of chronic bronchitis

STUDY OBJECTIVES: To compare the effectiveness of oral moxifloxacin with standard antibiotic therapy in acute exacerbation of chronic bronchitis (AECB). DESIGN: Multicenter, multinational, randomized, double-blind study of two parallel treatment arms. PATIENTS: Outpatients >or= 45 years old with stable chronic bronchitis, smoking history of >or= 20 pack-years, two or more AECBs in the previous year, and FEV(1) < 85% of predicted value. Patients were enrolled when in a stable condition, and patients with exacerbations within 12 months of enrollment were randomized. INTERVENTIONS: Randomization (stratified on steroid use) between moxifloxacin (400 mg qd for 5 days) and standard therapy (amoxicillin [500 mg tid for 7 days], clarithromycin [500 mg bid for 7 days], or cefuroxime-axetil [250 mg bid for 7 days]). MEASUREMENTS: Assessment at enrollment, randomization (Anthonisen type 1 exacerbation), 7 to 10 days after treatment, and monthly until next AECB or up to 9 months. The primary efficacy variable was clinical success (sufficient improvement, no alternative antimicrobial therapy required) 7 to 10 days after therapy. Secondary predefined end points were clinical cure (return to pre-exacerbation status), further antimicrobial use, time to next AECB, and bacteriologic success. RESULTS: Three hundred fifty-four patients received moxifloxacin, and 376 patients received standard therapy. At 7 to 10 days after therapy, clinical success rates were similar in intention-to-treat (ITT) patients (95% confidence interval [CI], - 0.7 to 9.5) and per-protocol (PP) patients (95% CI, - 3.0 to 8.5). Moxifloxacin showed superior clinical cure rates over standard therapy in both ITT patients (95% CI, 1.4 to 14.9) and PP patients (95% CI, 0.3 to 15.6), and higher bacteriologic success in microbiologically valid patients (95% CI, 0.4 to 22.1). Fewer ITT patients required antimicrobials after treatment with moxifloxacin than standard therapy (p < 0.01). Time to next exacerbation was longer with moxifloxacin; median and mean times to new AECBs in ITT patients who did not require any further antibiotics were 131.0 days and 132.8 days in moxifloxacin, and 103.5 days and 118.0 days in standard therapy, respectively (p = 0.03). The occurrence of failure, new exacerbation, or any further antibiotic was less frequent in moxifloxacin-treated patients for up to 5 months of follow-up (p = 0.03). CONCLUSIONS: Moxifloxacin was equivalent to standard therapy for clinical success and showed superiority over standard therapy in clinical cure, bacteriologic eradication, and long-term outcomes.     

A comparison of the safety and efficacy of moxifloxacin (BAY 12-8039) and cefuroxime axetil in the treatment of acute bacterial sinusitis in adults. The Sinusitis Study Group

The aim of this multicentre, randomized study was to compare the efficacy and safety of moxifloxacin (BAY 12-8039), a new 8-methoxy fluoroquinolone, with that of cefuroxime axetil for the treatment of acute bacterial sinusitis in adults. Diagnosis was made on a range of clinical signs and symptoms combined with radiology and microbiology. A 400 mg dose of moxifloxacin was administered once daily for 7 days to 242 patients and 250 mg twice daily of cefuroxime axetil was administered to 251 patients for 10 days. The clinical success rate at the end of treatment in the evaluable population was significantly higher (96.7%) in the moxifloxacin group (204/211) than in the cefuroxime axetil group (204/225, 90.7%; 95% confidence intervals 1.5%; 10.6%). At follow-up the success rate in the moxifloxacin group was 90.7% and that for the cefuroxime axetil group was 89.2% (95% confidence intervals -4.3%; 5.4%). The predominant pathogens isolated were Streptococcus pneumoniae and Haemophilus influenzae, followed by Moraxella catarrhalis and Staphylococcus aureus. The bacteriological eradication rates were higher for moxifloxacin (94.5%, 103/109) than for cefuroxime axetil (83.5%, 96/115; 95% CI 3.6%; 19.7%). Only one S. pneumoniae infection persisted following moxifloxacin therapy in contrast with three in individuals on cefuroxime axetil. There were slightly more adverse events in the moxifloxacin group than in the cefuroxime axetil group, but there were fewer serious adverse events following moxifloxacin treatment (three vs. eight). The drug was discontinued because of adverse events in 14 moxifloxacin patients and in 11 cefuroxime axetil patients. Overall, in all assessments, moxifloxacin was at least as effective clinically and bacteriologically, and as well tolerated, as cefuroxime axetil in the treatment of acute sinusitis.     

Comparative Efficacies and Tolerabilities of Intravenous Azithromycin Plus Ceftriaxone and Intravenous Levofloxacin with Step-Down Oral Therapy for Hospitalized Patients with Moderate to Severe Community-Acquired Pneumonia

Objective: To compare the efficacy and tolerability of ceftriaxone plus azithromycin with those of levofloxacin in the treatment of hospitalized patients with moderate to severe community-acquired pneumonia (CAP). Design: Randomized, open-label multicenter trial with 1 : 1 treatment allocation in an inpatient setting. Patients: 212 male or female inpatients with a clinical diagnosis of CAP were included in the study. In each treatment group >50% of patients had a pneumonia severity index of IV or V. Interventions: Open-label treatment with either intravenous (IV) ceftriaxone 1g and IV azithromycin 500mg daily or IV levofloxacin 500mg daily. Patients who improved clinically were switched to oral follow-on therapy with either azithromycin 500 mg/day or levofloxacin 500 mg/day. At the clinician’s discretion, oral cefuroxime axetil was added to the treatment regimen of patients who received oral azithromycin if a macrolide resistant pneumococcal isolate was documented. Results: Overall, both study treatments were well tolerated. Favorable clinical outcomes in clinically evaluable patients were demonstrated in 91.5% of patients treated with ceftriaxone plus azithromycin and 89.3% (95% CI ?7.1%, 11.4%) of patients treated with levofloxacin at the end of therapy visit and in 89.2% and 85.1% (95% CI ?6.7%, 14.8%) patients, respectively, at the end of study visit. Bacteriological eradication rates for both treatments were equivalent with the exception of Streptococcus pneumoniae; 44% of isolates were eradicated with levofloxacin compared with 100% of isolates with ceftriaxone plus azithromycin. Conclusions: As acknowledged by international CAP treatment guidelines, the combination of a third-generation cephalosporin and a macrolide is at least as efficacious as monotherapy with a fluoroquinolone with enhanced anti-pneumococcal activity, for hospitalized patients with moderate to severe CAP. Combined medication with a macrolide and third-generation cephalosporin may be preferred over fluoroquinolones as first-line therapy of hospitalized patients with CAP to minimize the development of multiresistant nosocomial Gram-negative bacilli.     

Treatment of community-acquired pneumonia in adults

Appropriate antibiotic treatment reduces the duration of symptoms associated to pneumonia, the risk of complications and mortality. In most cases, it is not possible to identify the etiologic agent so antibiotic treatment is empirically prescribed. In Chile, one third of Streptococcus pneumoniae strain isolates has diminished susceptibility to penicillin; in-vitro erythromycin resistance is about 10-15% and cefotaxime resistance 2-10%. It is recommended to classify patients with community acquired pneumonia in four risk categories: Group 1: patients under 65 years without co-morbidities, in ambulatory attendance. Treatment: oral amoxicillin 1 g TID, 7 days. Group 2: patients over 65 years and / or co-morbidities, in ambulatory attendance. Treatment: oral amoxicillin/clavulanate 500/125 mg TID or 875/125 mg BID, or cefuroxime 500 mg BID, 7 days. Group 3: patients admitted to general wards with criteria of moderate severity. Treatment: ceftriaxone 1-2 g once a day or cefotaxime 1 g TID, IV, 7-10 days. Group 4: patients with severe CAP that must be interned into ICU. Treatment: ceftriaxone 2 g once a day or cefotaxime 1 g TID, IV, associated to erythromycin 500 QID, levofloxacin 500-1.000 mg once a day, or moxifloxacin 400 mg/once a day, IV, 10-14 days. In the presence of allergy to or treatment failure with betalactam drugs and/or positive serology for Mycoplasma, Chlamydia or Legionella sp it is recommended to add: erythromycin 500 mg QID, IV or oral, oral clarithromycin 500 mg BID, or oral azythromycin 500 mg once a day.     

Short-course moxifloxacin therapy for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group

Chronic bronchitis is common among adults and infectious exacerbations contribute considerably to morbidity and mortality. We aimed to compare the safety and efficacy of moxifloxacin to clarithromycin for the treatment of patients with acute bacterial exacerbations of chronic bronchitis (ABECB) using a prospective, randomized, double-blind, parallel group trial. Between November 21, 1996 and April 7, 1998, 936 patients with acute exacerbations of chronic bronchitis (AECB) were enrolled at 56 centers across the United States of which 491 (52%) had ABECB (i.e. pretherapy pathogen). Patients were randomized to either oral moxifloxacin 400 mg administer once daily, for either 5 or 10 days, or clarithromycin 500 mg bid for 10 days. For the purpose of study blinding, the patients taking moxifloxacin received placebo to maintain uniform dosing. The main outcome measures were bacteriological response at the end of therapy (post-therapy days 0-6) and follow-up (7-17 days post-therapy) visits, as well as overall clinical response, clinical response at the end of therapy and clinical response at follow-up. Two patient populations were analyzed: efficacy-valid (i.e., those with a pretherapy pathogen) and intent-to-treat (i.e., all subjects that took drug). In 420 efficacy valid patients with a pretherapy organism, overall clinical resolution was 89% for 5 days moxifloxacin vs. 91% for 10 day moxifloxacin vs. 91% for 10 day clarithromycin. Bacteriological eradication rates at the end of therapy were 94% and 95% for 5-day moxifloxacin and 10-day moxifloxacin, respectively, and 91% for the clarithromycin group. Eradication rates at follow-up were 89% and 91% for 5-day moxifloxacin and 10-day moxifloxacin respectively, and 85% for the clarithromycin group. Among 926 intent-to-treat patients (312 5-day moxifloxacin, 302 10-day moxifloxacin and 312 clarithromycin), drug-related events were reported for 26%, 30% and 35%, respectively. Moxifloxacin 400 mg once daily, as a 5 or 10 day regimen, was found to be clinically and bacteriologically equivalent to 10 day clarithromycin for the treatment of ABECB. Given its favorable safety and tolerability profile, moxifloxacin administered once daily for 5 days may be as effective and a more convenient treatment than a standard course of clarithromycin for patients with ABECB.     

The integrated use of pharmacokinetic and pharmacodynamic models for the definition of breakpoints

For fluoroquinolones AUC/MIC ratios are known to correlate with clinical outcomes for patients suffering from respiratory tract infections (RTI) and complicated skin and skin structure infections (cSSSI). This paper describes the results of a population PK/PD analysis followed by Monte Carlo simulations to estimate clinical outcome and the microbiological breakpoints for a 400 mg once-daily moxifloxacin (MFX) treatment schedule. Based on PK data from 416 subjects, a non-compartmental population PK model was developed first to describe the expected exposure (AUC) distribution in humans. Height and gender were the main population covariates with moderate influence on PK variability. Albumin, bilirubin, and creatinine clearance (as derived from serum creatinine according to Cockroft and Gault) had a mild effect on AUC. Residual unexplained variability of AUC was low (13.1%). To describe the PD function the MIC distribution pattern of more than 3,000 isolates of S. pneumoniae as the representative pathogen for RTI (MIC90, range: 0.125; 0.006-4 mg/l) was built into the population PK/PD model for RTI, while 126 isolates of methicillin-susceptible Staphylococcus aureus strains (MIC90, range: 0.125; 0.03-4 mg/l) were the basis for the PD function in cSSSI. Simulations for 20,000 (RTI) and 4,000 (cSSSI) subjects were performed to evaluate the AUC/MIC characteristics for moxifloxacin for these two diseases. Overall, a target hit rate was THR = 99% for RTI, while it amounted to THR = 97.5% for cSSSI when applying a threshold of AUIC > 30 [h] as the PK/PD surrogate parameter which is predictive for a positive clinical outcome. A target hit rate of THR = 93.6 % (RTI) and 97.3% (cSSSI), respectively, was predicted when assuming that an AUIC of > 125 [h] is indicative of clinical success (as shown for ciprofloxacin and severe RTIs due to gram-negative infections). In clinical trials with patients receiving 400 mg moxifloxacin once daily for the treatment of community-acquired pneumonia (CAP) success rate was approximately 93.5%. From the simulations performed for RTI an analysis of the overall likelihood of therapeutic failure broken down according to MICs suggests that the risk of a negative clinical outcome at a MIC = 1 mg/l is approximately 0.25% (for MIC = 2 mg/l: predicted likelihood approximately 0.5%) assuming that a cutoff of AUIC = 30 [h] is applicable. Likewise, for cSSSI the probability to fail is predicted as 1.6% at a MIC = 2 mg/l (no strains with MICs between 0.5 and 1 mg/l available from the clinical isolates). These findings are in line with the breakpoint definition of the former National Committee for Clinical Laboratory Standards (NCCLS) for MFX (=1 mg/L to differentiate between susceptible and intermediately susceptible microorganisms; = 2 mg/l to separate intermediate from resistant pathogens). The results of the investigation indicate that the noncompartmental PK/PD model for MFX is suitable to predict clinical outcomes in CAP and cSSSI caused by gram-positive aerobe pathogens. They confirmed that a 400 mg once-daily dosing regimen is suitable to treat these diseases successfully. They are in agreement with the microbiological breakpoints determined by independent methods by the Clinical and Laboratory Standards Institute (CLSI) (former NCCLS).     

Sequential therapy with cefuroxime and cefuroxime-axetil for community-acquired lower respiratory tract infection in the oldest old

BACKGROUND AND AIMS: Community acquired lower respiratory tract infection (CALRTI) is the most common infection requiring hospitalization in the elderly. Sequential antibiotic therapy offers the potential for earlier functional rehabilitation, shorter length of hospital stay and lower costs. We studied the efficacy and safety of an empiric sequential antibiotic therapy with cefuroxime-cefuroxime axetil in elderly patients hospitalized with a CALRTI. METHODS: A prospective, randomized, open-label, in-hospital study of cefuroxime IV 750 mg tid for 10 days (IV group) vs cefuroxime 750 mg IV tid for 3 days, followed by cefuroxime-axetil PO 500 mg bid for 7 days (sequence group), when clinical (symptoms improved and fever disappeared) and/or laboratory response [decrease in C-reactive protein (CRP)] occurred. RESULTS: A total of 142 patients, 71 (mean age: 83.3 (+/-6 SD), M/F ratio: 1.1) in the IV group, and 71 (mean age: 81.5 (+/-7 SD), M/F ratio: 1.5) in the sequence group, were included in the study. Eighty-three (58.4%) presented with radiologically confirmed pneumonia (CAP) and 59 (41.6%) with non-pneumonic LRTI (NPLRTI) (p=ns between study groups). Treatment was considered effective in 84.5% (60/71) of patients in the IV group and 80.3% (57/71) in the sequence group (p=ns). Therapy failed in 15% (21/142) of the study population (p=ns between study groups) and, after day 3 of therapy, 8.45% (6/71) failed in both study groups. By the end of treatment, two patients had died in each study group, and total in-hospital mortality was 8.5% (12/142, p=ns between study groups). The length of hospital stay (LOS) did not differ between the two study groups. CONCLUSIONS: When a favorable clinical or biochemical response occurs on day 3 of IV cefuroxime therapy, further therapy with oral cefuroxime-axetil is as effective and safe as a full course of cefuroxime IV in elderly patients hospitalized with CALRTI. However, LOS was not reduced after sequential antibiotic therapy in this population.     

Pneumonia: still the old man's friend?

BACKGROUND: Hospital mortality of patients admitted with community-acquired pneumonia (CAP) has been well described. However, the long-term survival of those discharged alive is less clear. We sought to determine long-term survival of patients hospitalized with CAP and compare the outcome with controls hospitalized for reasons other than CAP. METHODS: We performed a matched case-control analysis using the Medicare hospital discharge database from the first quarter of 1997. We compared all Medicare recipients 65 years or older hospitalized with CAP and controls matched for age, sex, and race hospitalized for reasons other than CAP. We measured 1-year mortality determined from the Medicare Beneficiary Entitlement file and the Social Security Administration. RESULTS: We identified 158 960 CAP patients and 794 333 hospitalized controls. Hospital mortality rates for the CAP cohort and hospitalized controls were 11.0% and 5.5%, respectively (P<.001). One-year mortality rates for the CAP cohort and hospitalized controls were 40.9% and 29.1%, respectively (P<.001). One-year mortality rates in hospital survivors of the CAP and control cohorts were 33.6% and 24.9%, respectively (P<.001). The difference in mortality between the CAP and control cohorts was not explained by underlying disease. Standardized against the general population, the risk of death for both cohorts decreased monthly but was still elevated 1 year after hospital discharge. The standardized mortality ratio was 2.69 (95% confidence interval, 2.47-2.93) for CAP patients and 1.93 (95% confidence interval, 1.79-2.08) for hospital controls. CONCLUSIONS: Almost half of all elderly patients admitted for CAP die in the subsequent year, with most deaths occurring after hospital discharge. The mortality is considerably higher than that of either the general population or a control population hospitalized for reasons other than CAP.     

Long-term moxifloxacin in complicated tuberculosis patients with adverse reactions or resistance to first line drugs

STUDY OBJECTIVES: To test safety and tolerability of long-term moxifloxacin in resistant tuberculosis (TB) patients and patients with intolerance to first line anti-TB drugs. DESIGN: Clinical evaluation of adverse events (AEs) during prolonged moxifloxacin treatment. SETTING: TB Unit of the Regional TB Reference Center, Villa Marelli Institute, Niguarda Ca'Granda Hospital, Milan, Italy PATIENTS AND INTERVENTIONS: Patients treated with moxifloxacin, 400 mg orally once daily for TB in the Villa Marelli Institute from January 2001 to December 2003 were enrolled. RESULTS: Thirty-eight patients were treated with moxifloxacin at the Villa Marelli Institute in the study period, for multidrug resistant (MDR) TB (14, 36.8%), for intolerance to first line anti-TB drugs (9, 23.7%), for combined resistance and intolerance to first line anti-TB drugs (12, 31.6%), other reasons (3, 7.9%). The mean duration of moxifloxacin treatment was 6.3 +/- 5.2 months. Twelve (31.6%) patients reported at least an AE due to moxifloxacin, mostly gastrointestinal (8, 21.0%), general (5, 13.2%) and central nervous system (3, 7.9%) AEs. In 4 (10.5%) patients the drug was withdrawn for major AEs; no irreversible or fatal events were recorded. Most of the patients (31, 81.6%) reported a treatment success, even if the success rate was lower in MDR TB patients (8/14, 51.7%). CONCLUSIONS: Despite the fact that a large proportion of patients experienced at least an AE due to moxifloxacin, the drug resulted safe in the long-term administration for complicated TB cases.     

Etiology and outcome of community-acquired pneumonia in relation to age and severity in hospitalized adult patients]

The aim of this study was to determine the etiology and outcome of community-acquired pneumonia (CAP) in relation to age and severity in hospitalized patients. Overall, 652 consecutive patients with CAP were studied retrospectively during a 4-year period from 2002. Severity of pneumonia was classified according to the guidelines of the Japanese Respiratory Society (JRS 2005) and American Thoracic Society (ATS 2001). The etiology was identified in 401 of 652 (61.5%) cases. The four most frequent pathogens were Streptococcus pneumoniae (26.2%), influenza virus (12.4%), Mycoplasma pneumoniae (10.9%), and Haemophilus influenzae (5.9%). The most common pathogen in the younger (15-44 years) group and very severe patients (JRS) was Mycoplasma pneumoniae (38.4%) and influenza virus (28.6%), respectively. The three most frequent pathogens in severe CAP patients (ATS) were Streptococcus pneumoniae (29.0%), influenza virus (17.4%), and Legionella species (13.0%). The overall mortality was 6.4%. The mortality of CAP patients among aged 1544, 45-64, 65-74, and 75 years or older was 1.4%, 3.3%, 6.9% and 9.3%, respectively. The mortality of mild, moderate, severe, and very severe patients (RS) was 0%, 4.1%, 15.5%, and 53.6%, respectively. The mortality of non-severe and severe patients (ATS) was 1.8% and 23.9%, respectively. Age and severity had influence on the prevalence of the main microbial pathogens. Streptococcus pneumoniae remained the most important pathogen that needs consideration in initial antibiotic therapy in patients with CAP of all ages and severities. Pathogens identified in patients with severe CAP in Japan were similar to those of Western countries, except for the high incidence of the influenza virus.