The oxazolidinones inhibit bacterial protein synthesis by binding to the bacterial 23S rRNA of the 50S subunit, [208, 209] which blocks the interaction between charged tRNAs at the P site and the A site (Fig. 16) [210]. Specifically, LZD disrupts initiation of protein synthesis by inhibiting peptide bond formation between the carboxyl terminus of the N-formylmethionine-tRNA complex residue bound at the P site and the amino terminus of the amino acid-tRNA bound at the A site [210]. Crystal structures show LZD bound near the A site of the 50S ribosomal subunit at the 23S rRNA in such a way that peptide bond formation should be inhibited [211].

LZD-resistant tuberculosis has been observed in both following in vitro selection [212] and clinical strains (occurring only rarely) [213] and may arise through an active efflux system [214]. Many reports have shown that LZD is effective against MDR-TB both in vitro [215, 216] (MIC < 24 mM) and in vivo [51, 217, 218].

3.3.4 Clinical Use

For DA-7867 (15f), oral bioavailability in rats is 70.8%, with 8.3% not absorbed and 21.8% eliminated by intestinal first-pass metabolism [194]. LZD (15d) has nearly 100% bioavailability (regardless of whether or not it is taken with food [219]), and its half-life of 5.40 ± 2.06 h [220] allows for a 12-h dosing schedule

[221]. In healthy human subjects, steady-state plasma concentrations of 63 ± 17 mM are obtained at Tmax of 1.03 ± 0.62 h [220]. LZD's major metabolites (Fig. 17; 15l, 15m) are formed via oxidation alpha to the morpholine ring heteroatoms followed by ring opening [220]. It is metabolized through hepatic oxidation (and thus should not affect drugs metabolized by cytochrome P450 enzymes); hence, doses do not have to be altered for patients with renal or hepatic impairment [221]. LZD does not show suppressed antibiotic activity when coadministered with other antibiotics [221] and even shows synergistic activity with fluoroquinolones and RIF

[222]. PNU-100480 was studied in healthy volunteers (phase I clinical trials)[192, 193] and appeared to be well tolerated at doses of 1,000 mg/day [216]. Additionally, a whole blood assay against MTb showed PNU-100480 to be more effective

Linezolid major metabolic pathways

Excreted unmodified 42.4%±16.4% in urine 0.2±0.3% in feces



Presumed non- 9 " J.^ o enzymatic "-f ft II

PNU-100480 major metabolic pathway

Fig. 17 Metabolism of LZD (upper) [220] and PNU-100480 (lower)

than LZD, although doses of PNU-100480 used were higher (300 mg linezolid vs 1,000 mg PNU-100480 dosed daily until steady-state plasma concentrations were achieved) [216]. PNU-100480 forms metabolites by the oxidation of the sulfur atom (Fig. 17; 15n,o).

Side effects reported during phase III clinical trials of linezolid were generally not severe (however, the duration of exposure in such trials has been notably shorter than those used in MTb chemotherapy) [221]. More than half of the patients experienced digestive side effects (including constipation, diarrhea, vomiting, nausea), rash, headache, insomnia, or dizziness [221]. Hematological side effects including thrombocytopenia, anemia, leucopenia, or pancytopenia [221], although rare, warrant monitoring for longer treatment durations [223]. LZD can cause peripheral and optic neuropathy [221], and lactic acidosis has been reported in patients on longer treatment courses [221].

The largest (184 patients) retrospective analysis of patients empirically treated using LZD in a multidrug regimen for MDR- and XDR-TB patients in a multidrug regimen showed an overall 59% cure rate for the entire cohort, with an 87% cure rate in cases with definitive outcomes [224]. The use of LZD was also associated with a favorable outcome in a retrospective analysis of 176 XDR-TB-infected patients [62]. No prospective controlled data are available at this point although two trials are currently underway [53, 54].

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