A Comparison of the Toxic Effects of Two Oxazolidinones and Chloramphenicol on a Murine Erythroleukemia Cell Line
Knobloch, Hillary N.
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As a result of the frequent use of penicillin and other common antibiotics, numerous pathogens have developed mechanisms to evade these agents. Within the last twenty years, however, a promising new class of drugs has been in development that offers the potential to target bacteria that have become resistant to these antibiotics. This class, the oxazolidinones, is a novel class of antimicrobial agents that are bacteriostatic for Gram-positive bacteria, including those that are resistant to penicillin and other commonly used antibiotics (Diekema and Jones 2000). Target organisms for the oxazolidinones include methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus jaecium, among others (Swaney et al. 1998). The oxazolidinones exhibit a unique mechanism of action that enables their use for bacteria which are resistant to other antibiotics (Zurenko et ale 1996). Early studies with the oxazolidinones demonstrated that they inhibit bacterial protein synthesis, most likely at a step involving the binding of mRNA to the ribosome at the initiation of translation (Diekema and Jones 2000). The drugs do not affect RNA and DNA synthesis (Shinabarger et ale 1997), do not inhibit the formation of initiator tRNA, and do not block the elongation or termination steps of prokaryotic translation (Shinabarger et ale 1997). The binding of the oxazolidinones to the ribosomal site can be inhibited by chloramphenicol and lincomycin; however, the oxazolidinones appear to act through a mechanism that is distinct from the mechanisms of these drugs (Lin et al, 1997). Chloramphenicol and lincomycin act on the 50S subunit to inhibit the peptidyl transferase reaction and the translation termination reaction. Oxazolidinones have not been demonstrated to inhibit either peptidyl transferase or translation termination (Diekema and Jones 1997). Instead, the oxazolidinones bind directly to the 50S ribosomal subunit and prevent the formation of the 70S initiation complex in bacterial translation systems (Lin et al. 1997, Swaney et a1. 1998, Burghardt et a1. 1998). In early studies with the oxazolidinones, two compounds - eperezolid and linezolid - emerged with good potential to progress to clinical trials because of their significant in vitro activity against Gram-positive bacteria and their favorable toxicity profiles (Diekema and Jones 2000). These two compounds also displayed significant antibacterial activity in humans in vivo (Diekema and Jones 2000). Linezolid was developed over eperezolid because it exhibited superior pharmacokinetics in phase I trials in comparison with eperezolid (Diekema and Jones 2000). Recently, linezolid was approved by the United States Food and Drug Administration for the treatment of Grampositive skin and soft-tissue infection and community acquired pneumonia (Diekema and Jones 2000). Although linezolid has demonstrated an acceptable safety profile, dose- and timedependent, reversible myelosuppression were observed in preclinical animal studies. The myelosuppression was characterized by bone marrow hypocellularity, decreased hematopoiesis, and decreased levels of circulating reticulocytes, erythrocytes, leukocytes, and platelets. These effects occurred in both dogs and rats at exposure levels comparable to those that would be used in humans. While the bone marrow effects affected multiple lineages, the most principle effects seen in human clinical studies were decreased platelet counts. (U.S. Food and Drug Administration, NDA 21-130,31,32 and Package Insert 2000). Based on this information, the current research focuses on investigating the effects of two oxazolidinones on a murine erythroleukemia cell line (MEL C) as an in vitro model of bone marrow erthyroid progenitors.Missing pp. 23-36.