Linezolid is an oxazolidinedinone compound, a novel synthetic class that inhibits bacterial protein synthesis in a unique fashion via inhibiting the formation of the 70S initiation complex (50S and 30S ribosomes, mRNA, initiation factors 2 and 3, and fMet-tRNA) (83). The major properties of linezolid are summarized in Table 4. Linezolid exhibits a broad Gram-positive spectrum but has only bacteriostatic activity against VRE or VSE with an MIC90 of 2 mg/mL, which is right at the susceptibility breakpoint. FDA approval was granted in 2000 for vancomycin-resistant E. faecium infection, as well as for other site indications including community and nosocomial pneumonia, and CSSSI. Due to the lack of an approved comparator agent, linezolid was evaluated for patients with clinical and microbiologic evidence of serious VRE infection in a blinded parenteral dose-comparative trial comparing 66 patients randomized to 200 mg q 12 hr to 79 patients treated with 600 mg q 12 hr (84). Among evaluable patients at end-of-treatment, a modest dose response was observed with 67% and 52% response rates seen in the high-dose and low-dose groups, respectively. In addition, efficacy and safety was also demonstrated in a large study (n = 796 patients) emergency use program for resistant, treatment refractory, or intolerant patients with serious Gram-positive infection (85). Among 549 cases of VRE infection, there was an 81.4% clinical cure rate at end-of-therapy. Since linezolid is a bacteriostatic agent that displays no synergistic activity with other agents, its efficacy in VRE native-or prosthetic-valve endocarditis remains questionable. Both clinical success and failure have been reported when linezolid has been used as a first-line therapy or salvage treatment. However, no large-scale randomized trial experience is yet available (86-88).
In recent years linezolid has become the dominant agent for the treatment of serious VRE infection. Multiple reports of linezolid resistance (MIC > 8 mg/mL) occurring in VRE (E. faecium) and VSE (E.faecalis) strains that were susceptible (MIC 1 -2 mg/mL) at baseline but developed a four-fold or greater rise in MIC to 8 to 32 mg/mL (89-92). Common to most cases where linezolid resistance appeared has been a protracted length of therapy (> 28 days) associated with retained foci of VRE infection, such as abscesses, devitalized tissue, or foreign materials. The majority of linezolid-resistant isolates contain a single base-pair mutation in the genome encoding for domain V of the 23S ribosomal-binding site (G2476U mutation). The phenotypic level of resistance as determined by elevation in MIC level has been shown to correlate with the "gene dose" or number of copies 23S rDNA containing the G2466U mutation (93). Notably, this mutation was predicted by earlier in vitro spiral plate serial passage experiments with linezolid (94). Horizontal cross-transmission of an identical clone of linezolid-resistant E. faecium among linezolid-naive patients within the same ICU or hospital center have also been described (95,96). A case-control study revealed that a longer course of linezolid (38 vs. 11 days) and linezolid exposure prior to hospitalization were risk factors for the emergence of linezolid-resistant VRE (97). Thus, repeat linezolid susceptibility testing is advisable in patients who have had prior linezolid exposure, persistent isolation of a VRE strain on therapy, or in patients treated in a nosocomial setting with prior linezolid resistance.
Although gastrointestinal symptoms are the most common reported toxicity, reversible myelosuppression (thrombocytopenia, leukopenia, and/or anemia) has been the most important treatment-limiting side effect, with higher rates observed than the original registration studies. Bone marrow examination has shown changes similar to those observed with reversible chloramphenicol toxicity (98,99). Such toxicity is usually observed only with linezolid treatment that exceeds 2 weeks. Other reported toxicities of note include gastrointestinal upset, rare cases of serotonin syndrome, optic and peripheral neuropathy, and lactic acidosis (100-103).
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