Wednesday, January 10, 2018

Quick and Dirty Review: Linezolid

ID in the ED

Quick and dirty review: Linezolid

Drug shortages and intravenous fluid shortages are reaching critical mass. Pharmacotherapeutic decisions are being forced, and unusual therapeutic strategies are being implemented. One of these scenarios is the substitution of vancomycin for linezolid for empiric treatment of various infectious disease indications. While a detailed therapeutic review would be more fitting for general practice, the bizzaro world of drug shortages is anything but general. So let’s review linezolid for vancomycin substitution in these strange times.

What is linezolid
Linezolid belongs to the oxazolidinone therapeutic class, of which the only other currently available member is tedizolid.  Unlike other antibiotic classes, like penicillins, the oxazolidinones are fully synthetic compounds. Their mechanism of action is as a protein synthesis inhibitor, targeting the 23S rRNA of the 50S subunit and preventing the formation of a functional 70S initiation  complex.1 This mechanism of protein synthesis inhibition may also decrease toxin production in necrotizing skin and soft tissue infections (SSTI) due to toxin producing strains.

Spectrum of Activity1
The spectrum of activity of linezolid is limited primarily to gram positive bacteria, including: Streptococci (Group A, B, C, G), coagulase-positive Staphylococci (MRSA, MSSA), coagulase-negative Staphylococci, Enterococci (including VRE), Corynebacterium spp, Listeria monocytogenes, Peptostreptococci and Clostridium spp.

Linezolid is FDA approved for vancomycin-resistant Enterococcus faecium (VRE) infections, nosocomial pneumonia, community-acquired pneumonia, and skin and skin structure infections.

PK/PD
It’s rapid and extensive absorption (oral bioavailability ~ 100 %) allows for 1:1 IV to PO conversion. Distributes widely to well-perfused tissues (Vd = 0.6–0.7 L/kg). Linezolid is metabolized via hepatic oxidation of the morpholine ring to inactive metabolites, and excreted in the urine 30% as parent drug, 50% as metabolites. It’s normal half-life is ~ 4-5 hours, but these metabolites may accumulate in significant renal insufficiency (although it is eliminated by hemodialysis).

Adverse events of significance
Serotonin syndrome1-2
Linezolid is a weak, nonspecific monoamine oxidase inhibitor. As such, any concomitant serotonergic drug can increase the risk of serotonin syndrome. It’s recommended that any offending agent be held for at least 2 weeks prior to initiation of linezolid, but this may not be practical for most patients in the ED. In reality, discontinuation of the serotonergic agent and monitoring for 24 hours after discontinuation of linezolid is a reasonable strategy. It is worth noting that serotonin syndrome has been reported despite stopping the serotonergic agent days prior to initiation of linezolid due to a prolonged serotonergic agent half-life.

Serotonin modulators that have been implicated in case reports include: SSRIs, SNRIs, TCAs and a series of others agents such as bupropion, fentanyl, lithium, methadone, metoclopramide, mirtazapine, risperidone, tramadol, and trazodone.

Mitochondrial toxicities3-5
Some data indicates linezolid directly inhibits intramitochondrial protein synthesis. Linezolid seems to disrupt cellular energy production in tissues that are highly dependent on oxidative phosphorylation. It appears that linezolid may bind to the 16S ribosomal subunit in mitochondrial DNA, which is a region homologus to the linezolid binding site of the bacterial 23S rRNA. This interference with mitochondiral function has led to several clinically relevant adverse events: peripheral and optic neuropathy, lactic acidosis, and myelosuppression.

Peripheral and optic neuropathy1,5
A concerning consequence of mitochondrial toxicity is irreversible peripheral and optic neuropathies. Prolonged treatment durations greater than 28 days is the most pertinent risk factor for developing neuropathy. While this adverse effect is unlikely to sway decision making in the ED setting it is worth being aware of if patients present with these symptoms in the setting of prolonged linezolid courses.

Lactic Acidosis
Although rare, lactic acidosis has been reported with linezolid; mostly with prolonged durations of use. Patients with recurrent nausea and vomiting, acidosis, or low unexplained bicarbonate levels should be evaluated for linezolid-induced lactic acidosis. While this may not lead to any changes in the course of care in the ED, linezolid when combined with other medications that can impair lactate clearance (ie, epinephrine), it may impair the ability to trend lactate levels as a clinical measure. It may be relevant also in patients who are already on longer courses of linezolid as an outpatient and then present to the ED with signs/symptoms of lactic acidosis.

Myelosuppression6-8
Hematologic toxicity, primarily thrombocytopenia, but also including leukopenia, anemia, and pancytopenia have been associated with linezolid use. In phase-III clinical trials the incidence of thrombocytopenia was 2.4% in the linezolid treatment group, however multiple case studies have since found a higher incidence of up to 32%. These effects are thought to be time dependent, with thrombocytopenia occurring more frequently after 2 weeks of therapy, though they may occur earlier. Patients that appear to be at the highest risk for myelosuppression are those with lower baseline hematologic values, concomitant myelosuppressive agents, and those receiving extended durations of therapy. If consideration is given to initiating linezolid in the ED a CBC should be obtained. The good news is that myelosuppressive effects have been found to be reversible after discontinuation therapy.

Areas linezolid shines (when vancomycin is unable to be used)
  • Coverage of MRSA in pulmonary infections 
    • Linezolid remains active in pulmonary infections while daptomycin is inactivated by surfactant rendering it useless for this indication
  • VRE 
    • When used correctly, linezolid is a cornerstone of VRE therapy 
  • Necrotizing fasciitis
    • Since linezolid is a protein synthesis inhibitor it may decrease exotoxin production.Therefore, if you are treating necrotizing fasciitis with linezolid, you can omit clindamycin from your empiric regimen

Areas to use caution when using linezolid
  • Bacteremia, endocarditis, endovascular infection.
    • Given the bacteriostatic nature of linezolid it has typically been reserved for salvage therapy in these situations. (Though a systematic review was recently completed suggesting static vs cidal activity may not be as important as we originally thought.
    • In these situations daptomycin is a reasonable alternative to vancomycin
  • Urinary tract infection 
    • Only 30% active component is excreted into the urine limiting its efficacy (vs 78% for daptomycin)9

Other areas where linezolid may be used (when vancomycin is unable to be used)
  • SSTI
  • Meningitis
  • Bone/Joint infections
  • Intra-abdominal infections (Enterococcal coverage)

Take home points
  • When vancomycin is unable to be used, linezolid is an option to provide excellent gram-positive coverage in its place (including MRSA with the added benefit of VRE) 
  • Linezolid should be avoided for the empiric treatment of bacteremias, endocarditis, endovascular infections, and UTIs when possible
  • Linezolid has a unique adverse effect profile including serotonin syndrome, myelosuppression, and mitochondrial toxicities which may cause peripheral and optic neuropathies, as well as lactic acidosis
  • Stay tuned for future posts regarding daptomycin, another alternative to vancomycin, and how it compares to linezolid when vancomcyin cannot be used
  • Be sure to check your current supply of linezolid, as there was a recent recall due to white particulate matter that has been identified as mold. Specifically NDC 55150-242-51, batch CLZ160007, expiration August 2018, distributed May 15 through August 14, 2017.

Scott Dietrich, PharmD
@PCC_PharmD
Emergency Medicine Clinical Pharmacist
University of Colorado Health, North Region

Tony Mixon, PharmD, BCPS
@MixonMarkA
Emergency Medicine/Infectious Disease Clinical Pharmacist
University of Colorado Health, North Region

Craig Cocchio, PharmD, BCPS
@iEMPharmD
Emergency Medicine Clinical Pharmacist

Reference:

  1. Zyvox (linezolid) [prescribing information]. New York, NY: Pharmacia and Upjohn; July 2017
  2. Wigen CL1, Goetz MB. Serotonin syndrome and linezolid.Clin Infect Dis. 2002 Jun 15;34(12):1651-2. Epub 2002 May 23
  3. Palenzuela L, Hahn NM, Nelson RP Jr, et al. Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? [online exclusive article]. Clin Infect Dis 2005;40:e113–16. Available from http://www.journals.uchicago.edu/CID/journal/issues/v40n12/35321/35321.html
  4. De Vriese AS, Coster RV, Smet J, et al. Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis 2006;42:1111–17
  5. Narita, M., Tsuji, B. T. and Yu, V. L. (2007), Linezolid-Associated Peripheral and Optic Neuropathy, Lactic Acidosis, and Serotonin Syndrome. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 27: 1189–1197.
  6. Gerson SL, Kaplan SL, Bruss JB et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother. 2002 Aug;46(8):2723-6
  7. Minson Q, Gentry CA. Analysis of linezolid-associated hematologic toxicities in a large veterans affairs medical center. Pharmacotherapy. 2010 Sep;30(9):895-903.
  8. Attassi K, Hershberger E, Alam R, Zervos MJ. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002; 34(5):695-698
  9. Product Information: Cubicin(R) intravenous injection, daptomycin intravenous injection. Cubist Pharmaceuticals, Inc., Lexington, MA, 2010.


Featured Post

Giapreza - A Closer Look at the Pharmacology of Ang2

Angiotensin-II (Ang2) is now an FDA approved vasopressor. With this new addition to the available options, experts are combing over the ...