Targeting multidrug-resistant, gram-positive organisms

Learn about the mechanisms of action, spectrums, side effects, indications, and contraindications of daptomycin, linezolid, and tedizolid.

John F. Fisher, MD MACP FIDSA
John F. Fisher, MD MACP FIDSA
29th Jul 2019 • 3m read

Organisms such as MRSA and VRE are becoming more prevalent and more difficult to treat, but several newer drugs have been developed to target these resistant gram-positive strains. In this video, from our Antimicrobial Stewardship Essentials course, we'll cover the emerging problem of antibiotic resistance within many pathogens and the newer generation of gram-positive drugs that have been developed to try to combat this issue.

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Each day, patients die of bacterial infections for which no active agents are available. This course will familiarize you with the wide variety of antimicrobial agents available, as well as their mechanisms of action, spectrum of activity, and toxicity profiles so you can be more selective in choosing an agent when one is required and do your part to delay antimicrobial resistance.

Video Transcript

[00:00:00] Resistance of a number of gram-positive organisms to many antibacterial drugs has become a huge barrier to treating infections in recent years. In particular, organisms such as methicillin-resistant Staph aureus, MRSA, and vancomycin-resistant enterococcus, VRE, are becoming more prevalent and more difficult to treat. Several newer drugs have been developed

[00:00:30] recently to specifically target these resistant gram-positive strains. Linezolid and new tedizolid are ribosomal protein inhibitors. They bind to the ribosome and prevent the initiation of protein synthesis. The pharmacokinetics of tedizolid allow for once-daily dosing instead of twice daily required for linezolid. The principal uses for these agents is for infection suspected or proven

[00:01:00] to be due to resistant gram-positive pathogens such as MRSA and VRE. This may include skin and soft tissue infections and community or hospital-acquired pneumonia with or without bacteria. Because of bone marrow suppression and thrombocytopenia, peripheral and optic neuropathy and lactic acidosis, these agents are generally for short term use. Fewer low platelet

[00:01:30] counts and gastrointestinal side effects have been reported with tedizolid than with linezolid which aligns well with antimicrobial stewardship principles. linezolid therapy should ordinarily be prescribed in a hospital setting after examination by an infectious disease specialist. Part of the reason for an ID consultation is related to the potential toxicity of the compound. Linezolid therapy remains relatively

[00:02:00] expensive. Inappropriate use may induce the development of high-level linezolid resistance for mutations or acquisition of a resistance plasmid. In general, linezolid should be reserved for the treatment of MRSA infections as an alternative glycopeptides. Daptomycin is a large molecule that can accumulate in the cell membranes of susceptible gram-positive organisms leading the membranes

[00:02:30] to become porous or leaky and osmotically unstable and eventually leading to cell death. Daptomycin is a parenteral agent useful for staphylococcal bacteremia of unknown source especially MRSA and for right-sided infective endocarditis. It can also be used for complicated skin and soft tissue infections especially those resulting from suspected resistant gram-positive bacteria such as MRSA.

[00:03:00] It should not be used for pneumonia due to gram-positive organisms because it is inactivated by lung surfactant. Skeletal muscle toxicity and immune thrombocytopenia are the most common side effects associated with daptomycin. Patients taking this drug should undergo weekly monitoring of their creatine phosphokinase levels. The drug should be discontinued if the CPK levels rise more than 10 fold above normal or if a patient shows symptoms

[00:03:30] of myopathy and has a CPK level over 1000 IU / L. In patients with MRSA infections demonstrating reduced susceptibility to vancomycin, treatment with vancomycin has been associated with poor outcomes. An early switch to daptomycin may improve outcomes without increasing hospital costs in these patients.