CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m(2), the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II trials in patients with breast and renal cancer.

cIn 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.) H ospital-acquired pneumonia (HAP) remains an important problem in the care of critically ill patients and has significant clinical and economic consequences, including a 30% to 70% mortality rate (1-4). Mortality among patients with HAP associated with mechanical ventilation is approximately twice that of patients with HAP not associated with mechanical ventilation (5). The initial management of patients with HAP includes obtaining appropriate respiratory samples for culture and sensitivity and initiating therapy with broad-spectrum antibiotics that are active against likely pathogens (6).Tigecycline has a broad spectrum of antibacterial activity (7), including activity against many multidrug-resistant organisms and efficacy in treatment of community-acquired pneumonia (8-10). A single-dose study that collected lung tissue from uninfected subjects undergoing elective surgery showed a ratio of lung area under the concentration time-curve (AUC) to serum AUC, which is also known as lung penetration, of 2.0 (11). Results from a multiple-dose study with tigecycline that measured serum, pulmonary epithelial lining fluid (ELF), and alveolar cell concentrations in healthy volunteers demonstrated ELF penetration of 1.32 (12). These results, together with the observation by Crandon e...

A single 100 mg dose of intravenous tigecycline produced considerably higher tissue/fluid concentrations in bile, gall bladder, colon and lung compared with simultaneous serum concentrations. On average, the systemic exposure of tigecycline in bone, SF and CSF ranged from 11% to 41% of serum concentrations. The results in bone are inconsistent with previous radiolabelled studies in animals and it is unclear if tight binding to bone (versus low bone uptake) or poor extraction of tigecycline for LC/MS/MS detection or both may have contributed to the differences we observed in humans.

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In renal allograft recipients, SRL-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with continuation of CNI-based immunosuppression. This reduction was driven by a significant reduction in nonmelanoma skin carcinoma rates; the rate of all other malignancies was numerically lower but did not achieve statistical significance.