Safety and Efficacy of Tigecycline to Treat Multidrug-resistant Infections in Pediatrics: An Evidence Synthesis.

BACKGROUND: The need for antimicrobial therapies effective against multidrug resistant organisms for children remains unmet. Tigecycline shows antibacterial activity across a broad spectrum of bacteria and is approved for treating complicated skin and skin-structure infections, complicated intra-abdominal infections and, in the United States, community-acquired bacterial pneumonia for adult patients. No blinded, randomized phase 3 tigecycline clinical trials on neonates or children have been completed or planned. This review aimed to provide a comprehensive synthesis of all the existing data sources, both on-label and off-label, for tigecycline use in children. METHODS: Data on tigecycline use in children were identified from published and unpublished sources including clinical trials, expanded access and compassionate use programs, databases of healthcare records and patient safety monitoring. RESULTS: Pharmacokinetic simulations predicted that tigecycline 1.2 mg/kg (maximum dose 50 mg) every 12 hours (q12h) in children 8-11 years and 50 mg q12h in children 12 to <18 years would achieve exposure similar to adults receiving 50 mg q12h. Available phase 2 pediatric clinical trial data and data from other sources demonstrated similar clinical efficacy between adult and pediatric patients treated with tigecycline. These data showed no new or unexpected safety concerns with tigecycline in children. CONCLUSIONS: Information presented here may help guide the appropriate use of tigecycline in children with multidrug resistant infections. Continued pharmacovigilance from real-world observational studies may also further refine appropriate use of tigecycline.

A multicenter, double-blind, randomized, comparison study of the efficacy and safety of tigecycline to imipenem/cilastatin to treat complicated intra-abdominal infections in hospitalized subjects in China.

PURPOSE: To assess the efficacy and safety of tigecycline in treating complicated intra-abdominal infections (cIAIs) in hospitalized patients in China. PATIENTS AND METHODS: A Phase IV, multicenter, randomized, double-blinded, active-controlled, non-inferiority study was conducted. Hospitalized cIAI patients ≥18 years of age were randomized (1:1) to receive intravenous tigecycline (initial dose 100 mg, then 50 mg q12h) or imipenem/cilastatin (500 mg/500 mg or adjusted for renal dysfunction, q6h) for 5-14 days. The primary end point was clinical response for clinically evaluable (CE) subjects at test-of-cure (TOC) assessment. RESULTS: Four hundred and seventy subjects were randomized; 232 in the tigecycline and 231 in the imipenem/cilastatin group were treated. Tigecycline was non-inferior to imipenem/cilastatin with respect to clinical response at TOC for all CE subjects, ie, the lower bound of the two-sided 95% CI (-12.0%, -1.4%) for the treatment difference in cure rate, tigecycline (89.9%) minus imipenem/cilastatin (96.6%), was >-15%. As non-inferiority was concluded in the CE population, superiority of tigecycline over imipenem/cilastatin and superiority of imipenem/cilastatin over tigecycline were tested on the CE and the modified intent-to-treat (mITT) populations according to pre-specified statistical criteria, and neither could be demonstrated (the cure rate was 82.8% vs 88.7%, difference -6.0% [-12.8%, 0.8%], for the mITT population). The subject-level microbiological response rate at TOC for the microbiologically evaluable population was 88.0% (110/125) vs 95.3% (102/107, difference -7.3% [-15.2%, 0.5%]). Nausea, drug ineffectiveness, postoperative wound infection, vomiting, and pyrexia were the most common adverse events in tigecycline-treated subjects; pyrexia, nausea, vomiting, and increased alanine aminotransferase and aspartate aminotransferase levels were most common in imipenem/cilastatin-treated subjects; none were unanticipated. CONCLUSION: Tigecycline was non-inferior to imipenem/cilastatin in treating hospitalized adult patients with cIAI. Superiority of tigecycline over imipenem/cilastatin or imipenem/cilastatin over tigecycline could not be demonstrated. Safety was consistent with the known profile for tigecycline. CLINICALTRIALSGOV IDENTIFIER: NCT01721408.

Transfer ribonucleic acid charging in rat brain after consumption of amino acid-imbalanced diets.

Recognition of an amino acid-imbalanced diet (IMB) is thought to occur in the anterior piriform cortex (APC) of the brain in response to a decrease in the limiting amino acid. We hypothesized that tRNA charging is decreased after ingestion of IMB and that this is part of the mechanism by which a decrease in the limiting amino acid is recognized. We investigated this question by determining levels of charged and uncharged tRNA using the periodate oxidation method and also by using high performance liquid chromatography (HPLC) analysis of amino acids acylated to brain tRNA. Using the periodate method, we found that isoleucyl-tRNA in both whole brain and APC of rats fed an isoleucine-IMB was increased, rather than decreased, in comparison to the basal diet and the corrected diet. Using HPLC analysis, we found that the absolute amount of tRNA charged with the limiting amino acid was not altered by dietary treatment. These two experimental approaches measure different aspects of tRNA charging, but the results clearly indicate that a reduction in tRNA charging is unlikely to be the signal by which a limiting amino acid is recognized in the brain 2 h after ingestion of IMB.