Tigecycline versus levofloxacin in hospitalized patients with community-acquired pneumonia: an analysis of risk factors.

INTRODUCTION: This study was conducted to evaluate the efficacy of tigecycline (TGC) versus levofloxacin (LEV) in hospitalized patients with community-acquired pneumonia (CAP) using pooled data and to perform exploratory analyses of risk factors associated with poor outcome. MATERIALS AND METHODOLOGY: Pooled analyses of 2 phase 3 studies in patients randomized to intravenous (IV) TGC (100 mg, then 50 mg q12h) or IV LEV (500 mg q24h or q12h). Clinical responses at test of cure visit for the clinically evaluable (CE) and clinical modified intention to treat populations were assessed for patients with risk factors including aged ≥65 years, prior antibiotic failure, bacteremia, multilobar disease, chronic obstructive pulmonary disease, alcohol abuse, altered mental status, hypoxemia, renal insufficiency, diabetes mellitus, white blood cell count >30 x 10(9)/L or <4 x 10(9)/L, CURB-65 score ≥2, Fine score category of III to V and at least 2 clinical instability criteria on physical examination. RESULTS: In the CE population of 574 patients, overall cure rates were similar: TGC (253/282, 89.7%); LEV (252/292, 86.3%). For all but one risk factor, cure rates for TGC were similar to or higher than those for LEV. For individual risk factors, the greatest difference between treatment groups was observed in patients with diabetes mellitus (difference of 22.9 for TGC versus LEV; 95% confidence interval, 4.8 - 39.9). CONCLUSIONS: TGC achieved cure rates similar to those of LEV in hospitalized patients with CAP. For patients with risk factors, TGC provided generally favorable clinical outcomes.

Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia.

In a previous phase 3 study, the cure rates that occurred in patients with hospital-acquired pneumonia treated with tigecycline at the approved dose were lower than those seen with patients treated with imipenem and cilastatin (imipenem/cilastatin). We hypothesized that a higher dose of tigecycline is necessary in patients with hospital-acquired pneumonia. This phase 2 study compared the safety and efficacy of two higher doses of tigecycline with imipenem/cilastatin in subjects with hospital-acquired pneumonia. Subjects with hospital-acquired pneumonia were randomized to receive one of two doses of tigecycline (150 mg followed by 75 mg every 12 h or 200 mg followed by 100 mg every 12 h) or 1 g of imipenem/cilastatin every 8 h. Empirical adjunctive therapy was administered for initial coverage of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection, depending on the randomization regimen. Clinical response, defined as cure, failure of treatment, or indeterminate outcome, was assessed 10 to 21 days after the last day of therapy. In the clinically evaluable population, clinical cure with tigecycline 100 mg (17/20, 85.0%) was numerically higher than with tigecycline 75 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%). No new safety signals with the high-dose tigecycline were identified. A numerically higher clinical response was observed with the 100-mg dose of tigecycline. This supports our hypothesis that a higher area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) may be necessary to achieve clinical cure in patients with hospital-acquired pneumonia. Further studies are necessary. (The ClinicalTrials.gov identifier for this clinical trial is NCT00707239.).

Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia.

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

Efficacy and safety of tigecycline versus levofloxacin for community-acquired pneumonia.

BACKGROUND: Tigecycline, an expanded broad-spectrum glycylcycline, exhibits in vitro activity against many common pathogens associated with community-acquired pneumonia (CAP), as well as penetration into lung tissues that suggests effectiveness in hospitalized CAP patients. The aim of the present study was to compare the efficacy and safety of intravenous (IV) tigecycline with IV levofloxacin in hospitalized adults with CAP. METHODS: In this prospective, double-blind, non-inferiority phase 3 trial, eligible patients with a clinical diagnosis of CAP supported by radiographic evidence were stratified by Fine Pneumonia Severity Index and randomized to tigecycline or levofloxacin for 7-14 days of therapy. Co-primary efficacy endpoints were clinical response in the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (Day 10-21 post-therapy). RESULTS: Of the 428 patients who received at least one dose of study drug, 79% had CAP of mild-moderate severity according to their Fine score. Clinical cure rates for the CE population were 88.9% for tigecycline and 85.3% for levofloxacin. Corresponding c-mITT population rates were 83.7% and 81.5%, respectively. Eradication rates for Streptococcus pneumoniae were 92% for tigecycline and 89% for levofloxacin. Nausea, vomiting, and diarrhoea were the most frequently reported adverse events. Rates of premature discontinuation of study drug or study withdrawal because of any adverse event were similar for both study drugs. CONCLUSION: These findings suggest that IV tigecycline is non-inferior to IV levofloxacin and is generally well-tolerated in the treatment of hospitalized adults with CAP. TRIAL REGISTRATION: NCT00081575.

A Phase 3, open-label, non-comparative study of tigecycline in the treatment of patients with selected serious infections due to resistant Gram-negative organisms including Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae.

OBJECTIVES: To evaluate the efficacy and safety of tigecycline in patients with selected serious infections caused by resistant Gram-negative bacteria, or failures who had received prior antimicrobial therapy or were unable to tolerate other appropriate antimicrobials. Secondary objectives included an evaluation of the microbiological efficacy of tigecycline and in vitro activity of tigecycline for resistant Gram-negative bacteria. METHODS: This open-label, Phase 3, non-comparative, multicentre study assessed the efficacy and safety of intravenous tigecycline (100 mg initially, then 50 mg 12 hourly for 7-28 days) in hospitalized patients with serious infections including complicated intra-abdominal infection; complicated skin and skin structure infection (cSSSI); community-acquired pneumonia (CAP); hospital-acquired pneumonia, including ventilator-associated pneumonia; or bacteraemia, including catheter-related bacteraemia. All patients had infections due to resistant Gram-negative organisms, including extended-spectrum beta-lactamase-producing strains, or had failed on prior therapy or could not receive (allergy or intolerance) one or more agents from three classes of commonly used antibiotics. The primary efficacy endpoint was clinical response in the microbiologically evaluable (ME) population at test of cure (TOC). Safety data included vital signs, laboratory tests and adverse events (AEs). RESULTS: In the ME population at TOC, the clinical cure rate was 72.2% [95% confidence interval (CI): 54.8-85.8], and the microbiological eradication rate was 66.7% (95% CI: 13.7-78.8). The most commonly isolated resistant Gram-negative pathogens were Acinetobacter baumannii (47%), Escherichia coli (25%), Klebsiella pneumoniae (16.7%) and Enterobacter spp. (11.0%); the most commonly diagnosed serious infection was cSSSI (67%). The most common treatment-emergent AEs were nausea (29.5%), diarrhoea (16%) and vomiting (16%), which were mild or moderate in severity. CONCLUSIONS: In this non-comparative study, tigecycline appeared safe and efficacious in patients with difficult-to-treat serious infections caused by resistant Gram-negative organisms.

Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia.

Tigecycline (TGC), a glycylcycline, has expanded activity against Gram-positive and Gram-negative, anaerobic, and atypical bacteria. Two phase 3 studies were conducted. Hospitalized patients with community-acquired pneumonia (CAP) were randomized to intravenous (IV) TGC (100 mg followed by 50 mg bid) or IV levofloxacin (LEV) (500 mg bid). In 1 study, patients could be switched to oral LEV after at least 3 days intravenously. The coprimary efficacy end points were as follows: clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC). The secondary end points were as follows: microbiologic efficacy and susceptibility to TGC for CAP bacteria. Safety evaluations were included. Eight hundred ninety-one were patients screened: 846 mITT (TGC 424, LEV 422), 574 CE (TGC 282, LEV 292). Most patients had Fine Pneumonia Severity Index II to IV (80.7% TGC, 74.4% LEV, mITT). At TOC (CE), TGC cured 253/282 patients (89.7%) and LEV cured 252/292 patients (86.3%); the absolute difference of TGC-LEV was 3.4% (95% confidence interval [CI], -2.2 to 9.1, noninferior [P < 0.001]). In c-mITT, TGC cured 319/394 patients (81.0%) and LEV cured 321/403 patients (79.7%); the absolute difference of TGC-LEV was 1.3% (95% CI -4.5 to 7.1, noninferior [P < 0.001]). The drug-related adverse events (AEs) of nausea (20.8% TGC versus 6.6% LEV) and vomiting (13.2% TGC versus 3.3% LEV) were significantly higher in TGC; elevated alanine aminotransferase (2.8% TGC versus 7.3% LEV) and aspartate aminotransferase (2.6% TGC versus 6.9% LEV) were significantly higher in LEV. Discontinuations for AEs were low (TGC, 26 patients [6.1%]; LEV, 34 patients [8.1%]). TGC appeared safe and achieved cure rates similar to LEV in hospitalized patients with CAP.

Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial.

BACKGROUND & AIMS: Dilutional hyponatremia is a frequent complication of cirrhosis partly because of nonosmotic vasopressin release. No effective therapy exists for this complication. Therefore, we investigated the effects of VPA-985, an orally active vasopressin V2 receptor antagonist, in patients with cirrhosis and dilutional hyponatremia. Primary endpoint was normalization of serum sodium (serum sodium >or=136 mmol/L). METHODS: Sixty patients with cirrhosis and dilutional hyponatremia were randomly assigned to 100 or 200 mg/day of VPA-985 or placebo in a double-blind study. Treatment was given with fluid restriction (1000 mL/day) until normalization of serum sodium or for 7 days. RESULTS: Normalization of serum sodium concentration was achieved in 27% and 50% of patients in the VPA-985 100 mg/day and 200 mg/day groups, respectively, but in none of the patients in the placebo group (P < 0.05 and P < 0.001, respectively). Treatment with VPA-985 was associated with a significant reduction in urine osmolality and body weight. Thirst sensation increased significantly in the VPA 200 mg group but not in the VPA 100 mg or placebo group. Serious adverse events were similar among the 3 groups. CONCLUSIONS: An orally active vasopressin receptor antagonist can correct hyponatremia in patients with cirrhosis and ascites. This represents a novel therapy of water retention in cirrhosis.