Successful treatment of ventriculostomy-associated meningitis caused by multidrug resistant coagulase-negative Staphylococcus epidermidis using low-volume intrathecal daptomycin and loading strategy.

OBJECTIVE: To report successful use of low-volume intrathecal (IT) daptomycin and loading strategy for the treatment of ventriculostomy-associated meningitis. CASE SUMMARY: A 23-year-old man with a history of multiple ventriculoperitoneal shunt revisions resulting from multidrug-resistant Staphylococcus epidermidis shunt infection presented with meningitis despite suppressive antibiotic therapy. After source control surgery, the patient improved with intravenous daptomycin plus IT vancomycin. Then, 4 days later, significant ventriculostomy output occurred, and the S epidermidis was confirmed to be intermediately sensitive to vancomycin (MIC = 8 µg/mL) and susceptible to daptomycin (MIC = 2 µg/mL). IT vancomycin was changed to IT daptomycin 5 mg in 3 mL normal saline (NS) every 24 hours for 3 days, then every 72 hours for 18 days. The cerebrospinal fluid (CSF) was sterile after 1 day of IT daptomycin and remained so. Creatine kinase remained normal throughout the course of treatment. The patient was discharged on hospital day 50 without antibiotics. DISCUSSION: IT daptomycin has been reported for adult doses ranging from 5 to 10 mg once every 24 to 72 hours in volumes ranging from 5 to 10 mL; drug accumulation has been seen after the third dose of once every 24 hours dosing, and delayed improvement has been seen with once every 72 hours dosing. We planned for rapid load and CSF sterilization and extended the dosing interval once drug accumulation was expected to have occurred. CONCLUSIONS: IT daptomycin 5 mg diluted to 3 mL in NS and dosed in a loading strategy was effective and without adverse sequelae.

Discovery of Tirasemtiv, the First Direct Fast Skeletal Muscle Troponin Activator.

The identification and optimization of the first activators of fast skeletal muscle are reported. Compound 1 was identified from high-throughput screening (HTS) and subsequently found to improve muscle function via interaction with the troponin complex. Optimization of 1 for potency, metabolic stability, and physical properties led to the discovery of tirasemtiv (25), which has been extensively characterized in clinical trials for the treatment of amyotrophic lateral sclerosis.

Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

Discovery of omecamtiv mecarbil the first, selective, small molecule activator of cardiac Myosin.

We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.