Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

Background. Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods. TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results. Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). Conclusions. In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. Clinical Trials Registration. NCT02958709

Identification of Potential Dipeptide Inhibitors for PfENR Enzyme in Fatty Acid Biosynthesis Pathway II: A Computational Study for Developing Novel Antimalarials

803-806Malaria is a life-threatening disease caused by parasites of the genus Plasmodium that are transmitted through the bite of infected female Anopheles mosquitoes. The essential role of fatty acids in the malarial parasite's liver and blood stages makes it a promising target for combating P. falciparum. However, the emergence of strains of the malarial parasite has limited the efficacy of currently available drugs against malaria. Therefore, there is an urgent need to develop new drugs that can target the parasite and overcome drug resistance. This study aimed to identify potential dipeptide inhibitors for the PfENR enzyme using in-silico methods. Virtual screening was performed using thelibrary of 400 dipeptides to identify lead dipeptides with an affinity towards PfENR. We observed dipeptides Trp-Trp, Trp-Phe, Trp-Tyr, Tyr-Phe are showing the best affinity against PfENR. Density Functional Theory (DFT) analysis was used to reveal the electronic structure and reactivity of the top dipeptides by calculating the HOMO-LUMO gap. Additionally, we assessed the pharmacokinetic and other relevant properties of the lead dipeptides. All the lead dipeptides followed Lipinski's rule of five (Ro5). Our findings suggest that the identified dipeptides have significant potential as inhibitors of PfENR and could lead to the development of a novel class of antimalarial drugs. This research provides valuable insights into developing effective drugs to combat malaria