Linezolid Against Gram-Positive Bacterial Pathogens
abstract & commentary
Synopsis: Linezolid, a new oxazolidinone, shows promise in treating gram-positive infections.
Source: Noskin GA, et al. In vitro activities of linezolid against important gram-positive bacterial pathogens including vancomycin-resistant enterococci. Antimicrob Agents Chemother 1999;43:2059-2062.
The new class of antimicrobials known as the oxazolidinones has as its flagship entry a compound called linezolid. This class of agents acts by blocking formation of the so-called initiation complex at the 30S ribosome. Linezolid is bioavailable when given parenterally or orally. It is primarily active against gram-positive pathogens.
In this study from Noskin and colleagues at Northwestern Medical Center, a large number of gram-positive cocci—almost 4000—collected between April 1997 and March 1998 were tested against a panel of 12 gram-positive agents including linezolid.
The results showed that linezolid was consistently active with an MIC of 4 mcg/mL or less against Streptococcus pneumoniae, Enterococcus faecalis, and E. faecium, oxacillin-susceptible and oxacillin-resistant Staphylococcus aureus and S. epidermidis. Against E. faecium, linezolid was the most active agent; almost half of the 452 isolates tested were vancomycin-resistant. Linezolid was as active against vancomycin-resistant enterococci as it was against vancomycin-susceptible enterococci.
Against methicillin-resistant S. aureus (MRSA) the range of MICs was 0.5-4 mcg/mL; the MIC-90 for linezolid was 4 mcg/mL compared to 2 mcg/mL for vancomycin. Linezolid’s activity was the same against methicillin-resistant S. epidermidis, although we are not told if these isolates were rigorously speciated and we should assume that the 806 isolates tested were a composite of various coagulase-negative staphylococci.
Comment by joseph f. john, md
We need more agents to treat serious gram-positive infections. Linezolid is a promising compound as shown by this study, the largest sampling of linezolid’s activity against gram-positive pathogens. A large urban medical center, like the one at Northwestern University Medical School, may be a worst-case scenario for multiresistant microorganisms. In the face of such high-level resistance, linezolid performed as well as or better than available agents.
Trovofloxacin—a new fluoroquinolone now fallen from grace—was also tested in the panel of antimicrobial agents. For oxacillin-susceptible staphylococci, trovofloxacin was active as linezolid and against S. pneumoniae trovofloxacin was four times more active than linezolid. Until the new gram-positive agents like linezolid are market ready, trovofloxacin as shown in large in vitro trials like this one, still may play a niche role when the clinician has few other choices.
Based on preliminary pharmacokinetic data, the susceptibility breakpoint for linezolid will likely be set at 8 mcg/mL, above all the MIC90 results generated in this study. Current thinking holds that linezolid is not bactericidal, but it may, in fact, act through a slower bactericidal kill than we are used to determining. So, the verdict is still out on whether linezolid will be useful when a bactericidal agent is needed.
The millenium will witness the arrival of a series of gram-positive antimicrobial agents in addition to the oxazolinodones. After the debacle over trovofloxacin which hit the market with a nearly unblemished record, we will all tread cautiously as we gain experience with these new agents. If toxicity issues do not hamper the new agents, at the least we can hold hope from studies like the one from Noskin et al that the in vitro activity of agents like linezolid holds significant promise.
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