A phase 3, randomized, double-blind trial was conducted in subjects with diabetic foot infections without osteomyelitis (primary study) or with osteomyelitis (substudy) to determine the efficacy and safety of parenteral (intravenous [iv]) tigecycline (150 mg once-daily) versus 1 g once-daily iv ertapenem ± vancomycin. Among 944 subjects in the primary study who received ≥1 dose of study drug, >85% had type 2 diabetes; ~90% had Perfusion, Extent, Depth/tissue loss, Infection, and Sensation infection grade 2 or 3; and ~20% reported prior antibiotic failure. For the clinically evaluable population at test-of-cure, 77.5% of tigecycline- and 82.5% of ertapenem ± vancomycin-treated subjects were cured. Corresponding rates for the clinical modified intent-to-treat population were 71.4% and 77.9%, respectively. Clinical cure rates in the substudy were low (<36%) for a subset of tigecycline-treated subjects with osteomyelitis. Nausea and vomiting occurred significantly more often after tigecycline treatment (P = 0.003 and P < 0.001, respectively), resulting in significantly higher discontinuation rates in the primary study (nausea P = 0.007, vomiting P < 0.001). In the primary study, tigecycline did not meet criteria for noninferiority compared with ertapenem ± vancomycin in the treatment of subjects with diabetic foot infections.

This randomized, double-blind, multicenter study compared the efficacy and safety of piperacillin/tazobactam (P/T) and imipenem/cilastatin (IMP), both in combination with an aminoglycoside, in hospitalized patients with acute nosocomial pneumonia (NP). Patients with acute NP, defined as pneumonia with symptoms > or = 48 h after admission or < or =7 days after hospital discharge, received infusions of 4 g/500 mg P/T or 500 mg/500 mg IMP every 6 h. Endpoints were clinical cure and microbiological response rates; pathogen eradication rates; length of hospital stay; hospital readmissions; and adverse events (AEs). Of 437 patients in the intent-to-treat population, 197 were efficacy evaluable. At test-of-cure, response rates were similar between groups. Within the efficacy evaluable population, 68% of P/T patients and 61% of IMP patients were clinically cured (P = 0.256). Microbiological responses for P/T and IMP patients were: eradication, 64% versus 59%; persistence, 29% versus 21%; relapse, 0% versus 5%; and superinfection, 7% versus 15%, respectively. Gram-positive isolates were eradicated in 83% of P/T patients and 75% of IMP patients; Gram-negative pathogens were eradicated in 72% of P/T patients and 77% of IMP patients. Treatment groups had similar number of mean hospital days, readmission rates, and frequency of AEs. This study showed that P/T administered four times per day was as safe and efficacious as IMP in treating hospitalized patients with NP.

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In this non-comparative study, tigecycline appeared safe and efficacious in patients with difficult-to-treat serious infections caused by resistant Gram-negative organisms.

Tigecycline is a new-generation of tetracycline (glycylcyclines) and is active in vitro against bacteria that possess any of the classical genes that confer tetracycline resistance through ribosomal protection or efflux pumps. Herein, tigecycline disposition in patients with community-or hospital-acquired pneumonia was described using a population pharmacokinetic model. Additionally, the influence of covariates, such as body surface area, severity of illness, and clinical laboratory measures, on tigecycline disposition was evaluated. An intravenous loading dose of 100 mg was followed by 50 mg of tigecycline every 12 h. The final population pharmacokinetic model was a two-compartment model with linear elimination and with a relationship between tigecycline clearance and body surface area and creatinine clearance. The model was parameterized using total clearance (CL), the volume of the central compartment, distributional clearance from the central to the peripheral compartment, and volumes of distribution at steady state. Relationships between body surface area and creatinine clearance were identified as significant predictors of interindividual variability on CL. This model will serve as the basis for estimating tigecycline exposure for pharmacokinetic-pharmacodynamic analyses for efficacy and safety among patients with community-or hospital-acquired pneumonia.