Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study.

Clostridium difficile causes antibiotic-associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections, and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase and has potent activity against C. difficile and aerobic Gram-positive bacteria but little activity against Gram-negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults. Five cohorts of eight subjects each received CRS3123 or placebo in a 3:1 ratio. Doses for the respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. Blood and urine were collected for pharmacokinetic analysis. CRS3123 concentrations were measured with validated LC-MS/MS techniques. There were no serious adverse events or immediate allergic reactions during administration of CRS3123. In the CRS3123-treated groups, the most frequent adverse events were decreased hemoglobin, headache, and abnormal urine analysis; all adverse events in the active-treatment groups were mild to moderate, and their frequency did not increase with dose. Although CRS3123 systemic exposure increased at higher doses, the increase was less than dose proportional. The absorbed drug was glucuronidated at reactive amino groups on the molecule, which precluded accurate pharmacokinetic analysis of the parent drug. Overall, CRS3123 was well tolerated over this wide range of doses. This safety profile supports further investigation of CRS3123 as a treatment for C. difficile infections. (This study has been registered at ClinicalTrials.gov under identifier NCT01551004.).

Procalcitonin as a marker for the detection of bacteremia and sepsis in the emergency department.

Rapid diagnosis of bloodstream infections (BSIs) in the emergency department (ED) is challenging, with turnaround times exceeding the timeline for rapid diagnosis. We studied the usefulness of procalcitonin as a marker of BSI in 367 adults admitted to our ED with symptoms of systemic infection. Serum samples obtained at the same time as blood cultures were available from 295 patients. Procalcitonin levels were compared with blood culture results and other clinical data obtained during the ED visit. Procalcitonin levels of less than 0.1 ng/mL were considered negative; all other levels were considered positive. In 16 patients, there was evidence of BSI by blood culture, and 12 (75%) of 16 patients had a procalcitonin level of more than 0.1 ng/mL. In 186 (63.1%) of 295 samples, procalcitonin values were less than 0.1 ng/mL, and all were culture negative. With a calculated threshold of 0.1475 ng/mL for procalcitonin, sensitivity and specificity for the procalcitonin assay were 75% and 79%, respectively. The positive predictive value was 17% and the negative predictive value 98% compared with blood cultures. Procalcitonin is a useful marker to rule out sepsis and systemic inflammation in the ED.