ABSTRACT
The success of linezolid stimulated significant efforts to discover new agents in the oxazolidinone class. Over a dozen oxazolidinones have reached the clinic, but many were discontinued due to lack of differentiated potency, inadequate pharmacokinetics, and safety risks that included myelosuppression. Four oxazolidinones are currently undergoing clinical evaluation. The Trius Therapeutics compound tedizolid phosphate (formerly known as torezolid phosphate, TR-701, DA-7218), the most advanced, is in phase 3 clinical trials for acute bacterial skin and skin structure infections. Rib-X completed two phase 2 studies for radezolid (Rx-01_667, RX-1741) in uncomplicated skin and skin structure infections and community-acquired pneumonia. Pfizer and AstraZeneca have each identified antitubercular compounds that have completed phase 1 studies: sutezolid (PNU-100480, PF-02341272) and AZD5847 (AZD2563), respectively. The oxazolidinones share a relatively low frequency of resistance largely due to the requirement of mutations in 23S ribosomal RNA genes. However, maintaining potency against strains carrying the mobile cfr gene poses a challenge for the oxazolidinone class, as well as other 50S ribosome inhibitors that target the peptidyl transferase center.
Subject(s)
Anti-Bacterial Agents , Oxazolidinones , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/history , Anti-Bacterial Agents/pharmacology , Bacterial Infections/drug therapy , Clinical Trials as Topic , Drug Resistance, Bacterial/genetics , Genes, Bacterial , History, 20th Century , History, 21st Century , Humans , Mutation , Oxazolidinones/chemistry , Oxazolidinones/history , Oxazolidinones/pharmacologyABSTRACT
Significant progress in critical care medicine has been the result of tireless observation, dedicated research, and well-timed serendipity. This article provides a historical perspective for four meaningful therapies in critical care medicine: blood transfusion, fluid resuscitation, vasopressor/inotropic support, and antibiotics. For each therapy, key discoveries and events that have shaped medical history and helped define current practice are discussed. Prominent medical and social pressures that have catalyzed research and innovation in each domain are also addressed, as well as current and future challenges.
