Toxicity and Adverse Effects

3.3.2.6.1 Preclinical Toxicology. In dogs, the "no observed adverse effect, level" (NOAEL) of linezolid was 20 mg/kg for both sexes when administered orally for 28 days. Doses of 40 and 50 mg/kg/day were well tolerated with only mild effects. At toxic levels hy-pocellularity of the bone marrow (reversible decrease in white blood cells and platelets) and atrophy of the lymphoid tissue were observed.

3.3.2.6.2 Human Safety. Linezolid was well tolerated in human volunteers after oral or i.v. administration of daily doses up to 625 mg b.i.d. (349, 350, 360, 361). The most common adverse effects were nausea (5.4%), diarrhea (5.2%), or oral cavity symptoms (tongue discoloration, 2.5%; oral monilia, 2.2%). Serious drug-related adverse events (e.g., elevated liver enzymes, atrial fibrillation, or worsening renal failure) occurred in <1% of cases. In the linezolid compassionate-use trial of patients with significant, resistant Gram-positive infections, the overall adverse event rate was about 33%, of which approximately 6% were considered serious events (360). The most frequent adverse events reported were thrombocytopenia (2.6%) and dermatological reaction (2.5%) (361). Overall, at the end of therapy, linezolid was well tolerated by about 78% of patients (361).

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytope-nia) has been reported in three patients receiving linezolid for 2 and 6 weeks, and 4 months, respectively. With discontinuation of linezolid treatment, the affected hematological parameters rose toward pretreatment levels (362). The U.S. FDA has recommended that complete blood counts should be monitored weekly, particularly in patients who receive linezolid for longer than 2 weeks.

3.3.3 New Oxazolidinones. The special features of the antibacterial activity of oxazo-lidinones highlighted earlier attracted much

Considerable flexibility for substitution in this region

3-N-aryl group appears J / essential for activity o

3-substitution, imparts improved activity

A5-(S)-configuration necessary fix activity

Cd-amidomethyl group imparts improved activity

Figure 13.8. Oxazolidinones as antibacterials: important structural features.

attention. A number of reports have appeared describing new oxazolodinones with improved antibacterial activities. On the basis of the early structure-activity studies (321, 330), some structural features that appeared important for good antibacterial activity in oxazolidinones could be identified and are presented in Fig. 13.8(363).The diagrammatic representation in Fig. 13.8acted as a useful guide for subsequent studies and broadly still holds. The structure-activity relationship of the reported oxazolidinones (364) is presented in the context of this picture of the pharmacophore.

A-Ring Modification. The oxazolidinone ring structure seems essential for good antibacterial activity and relatively few successful modification of the A-ring have been reported (364). The tricyclic analogs having a methylene bridge between rings A and B have been reported, with the transfused trans homolog (80) having good activity (365, 366), although

the exact linezolid analog (81) was only weakly active. The 3-pyridyl analog (82) is the most active compound in this series (365).

B-Ring Modification. The replacement of the B-aromatic residue by heteroaromatic rings as in (83-87) gave compounds that had

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