Lala M. Dunbar

High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm.

Levofloxacin demonstrates concentration-dependent bactericidal activity most closely related to the pharmacodynamic parameters of the ratio of area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) and the ratio of peak plasma concentration (C(max)) to MIC. Increasing the dose of levofloxacin to 750 mg exploits these parameters by increasing peak drug concentrations, allowing for a shorter course of treatment without diminishing therapeutic benefit. This was demonstrated in a multicenter, randomized, double-blind investigation that compared levofloxacin dosages of 750 mg per day for 5 days with 500 mg per day for 10 days for the treatment of mild to severe community-acquired pneumonia (CAP). In the clinically evaluable population, the clinical success rates were 92.4% (183 of 198 persons) for the 750-mg group and 91.1% (175 of 192 persons) for the 500-mg group (95% confidence interval, -7.0 to 4.4). Microbiologic eradication rates were 93.2% and 92.4% in the 750-mg and 500-mg groups, respectively. These data demonstrate that 750 mg of levofloxacin per day for 5 days is at least as effective as 500 mg per day for 10 days for treatment of mild-to-severe CAP.

Telavancin Versus Standard Therapy for Treatment of Complicated Skin and Soft-Tissue Infections Due to Gram-Positive Bacteria

BACKGROUND Telavancin, a novel lipoglycopeptide, exerts concentration-dependent, rapid bactericidal activity on account of its multiple mechanisms of action. Telavancin is highly active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate, and vancomycin-resistant strains. METHODS We conducted a randomized, double-blind, controlled, phase-2 clinical trial. Patients > or = 18 years of age with a diagnosis of complicated skin and soft-tissue infection caused by suspected or confirmed gram-positive organisms were randomized to receive either intravenously administered telavancin once daily or standard therapy (antistaphylococcal penicillin 4 times daily or vancomycin twice daily). RESULTS For the study, 167 patients were randomized and received at least 1 dose of study medication. Success rates were similar in all analysis populations at the test-of-cure evaluation. Of patients with S. aureus infection at baseline (n = 102), 80% of the telavancin group were cured and 77% of the standard therapy group were cured. For patients with MRSA infection at baseline (n = 48), cure rates were 82% for the telavancin group and 69% for the standard therapy group. Microbiologic eradication in patients with MRSA infection was 84% for the telavancin group versus 74% for the standard therapy group. MIC90 values were lower for telavancin in all tested strains of S. aureus (< or = 0.25 ug/mL) compared with the MIC90 values for vancomycin and oxacillin. Similar proportions of patients discontinued therapy for adverse events in both treatment groups (approximately 5%). Fewer serious adverse events were reported in the telavancin group (4 events) than were for the standard therapy group (9). CONCLUSION Clinical and microbiological results of this study support the further development of telavancin, especially for treatment of infection due to MRSA.

Telavancin versus Standard Therapy for Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: FAST 2 Study

ABSTRACT Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients ≥18 years of age with complicated skin and skin structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin at 10 mg/kg intravenously every 24 h (q24h) or standard therapy (antistaphylococcal penicillin at 2 g q6h or vancomycin at 1 g q12h). A total of 195 patients were randomized and received at least one dose of study medication. Clinical success rates were similar in all analysis populations at test of cure. In microbiologically evaluable patients with Staphylococcus aureus at baseline (n = 91), 96% of the telavancin group and 90% of the standard-therapy group were cured. Among patients with methicillin-resistant S. aureus (MRSA) at baseline (n = 45), clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbiologic eradication in patients with S. aureus infection was better with telavancin compared to standard therapy (92% versus 78%, P = 0.07) and significantly better in patients with MRSA (92% versus 68%; P = 0.04). Therapy was discontinued for an adverse event (AE) in 6% and 3% of the patients receiving telavancin and standard therapy, respectively. Except for two cases of rash in the telavancin group, these AEs were similar in type and severity in the two groups. The overall incidences and severities of AEs and laboratory abnormalities were similar between the two groups. These data support the ongoing studies assessing the efficacy and safety of telavancin in the treatment of serious gram-positive infections, particularly involving MRSA.

Efficacy of 750-mg, 5-day levofloxacin in the treatment of community-acquired pneumonia caused by atypical pathogens

SUMMARY Background: Current recommended durations for treatment of atypical community-acquired pneumonia (CAP) range from 10 to 21 days. However, antibiotics such as the fluoroquinolones may allow for effective, short-course regimens. Objective: This study evaluated the efficacy of 750 mg levofloxacin for 5 days compared to a 500-mg, 10-day levofloxacin regimen for the treatment of atypical CAP. Methods: A randomized, active-controlled, double-blind, multicenter study was conducted within the United States. Of the 528 patients enrolled in the study, 149 were diagnosed with CAP due to Legionella pneumophila, Chlamydia pneumoniae, or Mycoplasma pneumoniae. Patients’ baseline symptoms were re-evaluated on Day 3 of therapy. Clinical efficacy and resolution of CAP symptoms were evaluated at the posttherapy visit (7–14 days after the last dose of active drug). Results: This report represents a subgroup analysis of a previous clinical study. Among the 123 clinically evaluable patients diagnosed with atypical CAP (26 patients were unevaluable), the clinical success rates were 95.5% (63 of 66 patients) for the 750-mg group and 96.5% (55 of 57 patients) for the 500-mg group (95% CI for success rate of the 500-mg group minus that of the 750-mg group, –6.8 to 8.8). At the poststudy evaluation (31–38 days after treatment began), relapse occurred in ≤ 2% of patients in either treatment group. Among patients diagnosed with atypical CAP, the 750-mg therapy resulted in more rapid symptom resolution, with a significantly greater proportion of patients experiencing resolution of fever by Day 3 of therapy ( p = 0.031). Conclusion: The 750-mg, 5-day course of levofloxacin was at least as effective as the 500-mg, 10-day regimen for atypical CAP. Additionally, the 750-mg, short-course levofloxacin therapy may reduce total antimicrobial drug usage and more rapidly relieve pneumonia symptoms.

Efficacy and tolerability of once-daily oral telithromycin compared with clarithromycin for the treatment of community-acquired pneumonia in adults

BACKGROUND Telithromycin is a new antibacterial agent of the ketolide class designed to provide optimal treatment against common bacterial respiratory tract pathogens. Telithromycin was derived by structural modification of the basic macrolide molecule to allow tight binding to the bacterial ribosome that enhances potency and minimizes the risk for the development of resistant strains. OBJECTIVE The aim of this study was to compare the efficacy and tolerability of telithromycin 800 mg once daily with those of high-dose clarithromycin (500 mg twice daily), each for 10 days, in the treatment of adult patients with community-acquired pneumonia (CAP). METHODS This randomized, double-blind, double-dummy, parallel-group clinical trial was conducted at 54 centers in the United States, Canada, Argentina, and Chile. Patients aged >or=18 years with acute CAP were randomized to receive 10-day treatment with oral telithromycin 800 mg once daily (administered as two 400-mg encapsulated tablets in the morning) and placebo (administered as 2 encapsulated tablets identical to the telithromycin in the evening) or high-dose clarithromycin (500 mg administered as two 250-mg identical encapsulated tablets twice daily). The primary outcome measure was clinical outcome at the posttherapy, test-of-cure visit (days 17-24 after the completion of therapy) in the clinically assessable per-protocol population. Secondary efficacy variables included bacteriologic outcome at the posttherapy, test-of-cure visit, and clinical and bacteriologic outcomes at the late posttherapy visit (day 31-45). Tolerability was assessed using investigator observation, patient self-reporting, clinical laboratory data, a 12-lead electrocardiogram, and physical examination (including vital signs). RESULTS A total of 493 patients were enrolled and 448 patients received >or=1 dose of study medication (224 patients/group). A diagnosis of CAP was confirmed in 416 patients (205 men, 211 women; median age, 43 years; telithromycin, n = 204; clarithromycin, n = 212). Clinical cure rates were 88.3% (143/162) in the telithromycin group and 88.5% ( 138/56) in the clarithromycin group. Bacterial eradication rates were comparable between treatment groups (telithromycin, (28/32) [87.5%]; clarithromycin, (29/30) [96.7%]. Both treatment were fairly well tolerated; adverse events were experienced in 57.0% of the patients treated with telithromycin and 49.1% of those treated with clarithromycin; most of these were assessed as mild. CONCLUSIONS In this study of adult patients with CAP, telithromycin 800 mg once daily was an effective and fairly well-tolerated regimen for initial empiric treatment, with clinical and bacteriologic efficacy and tolerability equivalent to therapy with high-dose clarithromycin (500 mg twice daily).

Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: An Analysis of the SIMPLIFI Trial

ABSTRACT Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA.

Effectiveness of levofloxacin for adult community-acquired pneumonia caused by macrolide-resistant Streptococcus pneumoniae: integrated results from four open-label, multicenter, phase III clinical trials.

BACKGROUND The rate of macrolide resistance among Streptococcus pneumoniae clinical isolates is rising. Coresistance to several unrelated classes of antimicrobial agents is common and may limit the treatment options available for the management of infections caused by this pathogen. Although the fluoroquinolones appear to retain activity against macrolide-resistant pneumococci, limited clinical data exist to support their use in this setting. OBJECTIVE This study integrated data from 4 clinical trials to determine whether the fluoroquinolone levofloxacin is an effective therapeutic agent for community-acquired pneumonia (CAP) caused by macrolide-resistant S. pneumoniae. METHODS Across the 4 trials, 271 adult patients with CAP were diagnosed with infections caused by S. pneumoniae; these constituted the intent-to-treat population. Clinical isolates obtained from each patient at admission were tested using broth microdilution for in vitro sensitivity to the macrolide erythromycin (minimum inhibitory concentration breakpoints: susceptible, < or =0.25 microg/mL; intermediate, 0.5 microg/mL; resistant, > or =1.0 microg/mL). All patients received levofloxacin (500 mg once daily for 7-14 days) and were analyzed at a posttherapy visit (2-5 days after completion of therapy) for clinical and microbiologic outcomes; in 3 trials, patients were also examined at a poststudy visit (14-28 days after completion of treatment). Clinical and microbiologic outcomes were analyzed in patients infected with macrolide-resistant and macrolide-susceptible S. pneumoniae. RESULTS A total of 235 evaluable patients infected with S. pneumoniae were identified from the 4 trials. Twenty-seven (11.5%) patients were infected with isolates resistant to erythromycin, of whom 26 (96.3%) were clinical successes. By comparison, the clinical success rate in patients infected with erythromycin-susceptible isolates was 97.7%. CONCLUSIONS These results suggest that if future studies demonstrate the clinical relevance of macrolide resistance, levofloxacin may be a useful therapeutic option in patients with CAP caused by macrolide-resistant S. pneumoniae. However, caution may be warranted to prevent overprescription of levofloxacin and other fluoroquinolones, given the potential for the development of resistance in S. pneumoniae.

A review of telavancin in the treatment of complicated skin and skin structure infections (cSSSI)

Telavancin is a novel antibiotic being investigated for the treatment of serious infections caused by Gram-positive bacteria, including complicated skin and skin structure infections (cSSSI) and pneumonia. This once-daily intravenous lipoglycopeptide exerts rapid bactericidal activity via a dual mechanism of action. It is intended for use to combat infections caused by Staphylococcus aureus and other Gram-positive bacteria, including methicillin-resistant and vancomycin-intermediate strains of S. aureus (MRSA and VISA, respectively). Vancomycin is the current gold standard in treating serious infections caused by Gram-positive bacteria, especially MRSA. In recent clinical trials, telavancin has shown excellent efficacy in phase II and III multinational, randomized, double-blinded studies of cSSSI. In the phase II FAST 2 study, which compared telavancin 10 mg/kg intravenously q 24 h vs standard therapy (an antistaphylococcal penicillin at 2 g IV q 6 h or vancomycin 1 gm IV q 12 h), the clinical success rate in the telavancin-treated group was 96% vs 94% in the standard therapy group. In two identical phase III trials comparing telavancin versus vancomycin at the doses of the FAST 2 study for cSSSI, the clinical cure rates were 88.3% and 87.1%, respectively. Two additional phase III clinical trials investigating telavancin for use in hospital-acquired pneumonia, caused by Gram-positive bacteria are currently ongoing. Telavancin is currently under regulatory review in both the United States and Europe for the indication of treatment of cSSSI.

Efficacy of telavancin in patients with specific types of complicated skin and skin structure infections

BACKGROUND Telavancin is approved in the USA and Canada for the treatment of Gram-positive complicated skin and skin structure infections (cSSSIs) based on the results of the Phase 3 Assessment of TeLAvancin in complicated Skin and skin structure infections (ATLAS) trials, which demonstrated non-inferiority of telavancin to vancomycin. METHODS We conducted a post hoc analysis of the ATLAS studies (ClinicalTrials.gov identifiers NCT00091819 and NCT00107978) to explore the efficacy of telavancin in patients with various types of cSSSIs. RESULTS A total of 1794 patients were included in this analysis; 1434 patients were clinically evaluable (CE) and 563 of these had methicillin-resistant Staphylococcus aureus (MRSA). Among CE patients with major abscesses (n = 619), cure rates were 91% for telavancin and 90% for vancomycin (95% CI for the difference -3.6 to 5.7). In patients with infective cellulitis (n = 519), cure was achieved in 87% and 88% of telavancin- and vancomycin-treated patients, respectively (95% CI for the difference -6.2 to 5.2). Cure rates in patients with wound infections were 85% in the telavancin group and 86% in the vancomycin group (95% CI for the difference -10.5 to 9.0). Cure rates for each type of cSSSI in patients infected with MRSA were also similar between the two treatment arms. Among CE patients infected with Panton-Valentine leucocidin (PVL)-positive MRSA (n = 447), cure rates were 93% for telavancin and 90% for vancomycin (95% CI for the difference -2.2 to 8.2). CONCLUSIONS Cure rates were similar for telavancin and vancomycin in patients with different types of cSSSIs, including infections caused by MRSA and PVL-positive strains of MRSA.

Efficacy of Telithromycin in Community-Acquired Pneumonia Caused by Pneumococci with Reduced Susceptibility to Penicillin and/or Erythromycin

Background: The efficacy of oral telithromycin was assessed in patients with community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae with reduced susceptibility to penicillin and/or erythromycin. Methods: Patients with CAP who had received telithromycin 800 mg once daily for 5 or 7–10 days (n = 2,289) in eight phase III clinical trials, or telithromycin 800 mg once daily for 7 days (n = 50) in a phase II study were included in this pooled analysis. Patients with S. pneumoniae as the cause of infection were identified, with particular focus on those infected with strains with reduced susceptibility to penicillin (intermediate, minimal inhibitory concentration (MIC) 0.12–1.0 mg/l; resistant, MIC ≧2.0 mg/l) and/or resistance to erythromycin (MIC ≧1.0 mg/l). Per-protocol clinical and bacteriological outcomes were assessed 7–14 days post-therapy in the phase III studies, and at 7–21 days post-therapy or at the end of therapy in the phase II study. Results: Of the 327 telithromycin-treated patients with S. pneumoniae infection, 61 (19%) were infected with strains with reduced susceptibility to penicillin and/or erythromycin. Clinical cure and bacterial eradication rates in these patients were 91.8% (56/61) and 93.4% (57/61), respectively. Corresponding clinical cure and bacterial eradication rates overall for all isolates of pneumococci were 94.5% (309/327) and 96.0% (314/327), respectively. All isolates with reduced susceptibility to penicillin and/or erythromycin were susceptible to telithromycin (MIC ≤1.0 mg/l). Conclusion: These results indicate that telithromycin is an effective oral antibacterial for the treatment of CAP caused by pneumococci with reduced susceptibility to penicillin and/or erythromycin.