Linezolid - Department of Microbiology Antimicrobial Prescribing Guidelines

Publication: 11/09/2017  
Last review: 01/01/1900  
Next review: 11/09/2020  
Clinical Guideline
CURRENT 
ID: 5155 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2017  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Department of Microbiology (Restricted) Antimicrobial Prescribing Guidelines

Linezolid

This document provides guidelines for healthcare professionals regarding the situations in which it would be appropriate to consider the use of linezolid. This document is supplementary to, and should be used in conjunction with, the summary of product characteristics.

The use of linezolid can be considered within its currently approved LTHT Drugs and Therapeutics Group [DTG] application; other indications will require chairman’s action.

DRUG INFORMATION
Introduction

Linezolid is an oxazolidinone antibacterial, with its mechanism of action brought about through inhibition of ribosomal protein synthesis1. Linezolid is also a reversible, non-selective monoamine oxidase inhibitor (MAOI) and therefore may potentiate the effects of MAOIs and related classes of antidepressants (See contraindications and interactions).

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Antimicrobial activity2

Susceptible organisms
Gram-positive aerobes:
Enterococcus faecalis
Enterococcus faecium
Staphylococcus aureus
Coagulase negative staphylococci
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Group C streptococci
Group G streptococci
Gram-positive anaerobes:
Clostridium perfringens
Peptostreptococcus anaerobius
Peptostreptococcus species

Resistant organisms
Haemophilus influenzae
Moraxella catarrhalis
Neisseria species
Enterobacteriaceae
Pseudomonas species

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Dose/Routes of administration1,2

DOSE

Oral
600mg every 12 hours

Intravenous Infusion
600mg every 12 hours (2mg/ml solution infused over 30 - 120 minutes)

Due to linezolid having 100% oral bioavailability IV linezolid is only usually required in patients with absorption issues, unable to take medications orally and severe sepsis.

DOSE ADJUSTMENT IN RENAL IMPAIRMENT/FAILURE1,2,3
In severe renal impairment, CrCL < 30ml/min, no dosage adjustment is required, but close monitoring for side effects including low platelets is recommended.

Linezolid is removed by dialysis and therefore the dose should be given post dialysis on dialysis days.

DOSE IN OBESITY
For concerns around treatment failure in obese patients please contact the pharmacy infection team.

DOSE IN LIVER FAILURE
No dosage adjustment is required. However, in severe hepatic impairment linezolid should only be used where the benefit outweighs the risk.

PAEDIATRIC DOSES2,4
Use of linezolid in neonates and paediatrics would be off-label and discussion with microbiology or infectious diseases is required.
Although off-label the BNF for children lists the following information regarding dosing in this population:

Neonate up to 7 days
10mg/kg every 12 hours, increased if necessary to 10mg/kg every 8 hours if poor response.

Neonate 7 to 28 days
10mg/kg every 8 hours

Child 1 month - 11 years
10mg/kg every 8 hours (max. per dose 600mg)

12-17 years
600mg every 12 hours

Note linezolid is licensed for the following indications:

  • community acquired pneumonia
  • nosocomial pneumonia
  • complicated skin and soft tissue infections

If gram-negative bacteria are also suspected then treatment against gram- negative organisms must be initiated concomitantly.
At LTHT some of the indications that linezolid is used for are off-label, however this is when other therapy may not be appropriate due to:

  • Intolerance
  • Failure of other therapy
  • Contraindications
  • Resistance

The evidence for linezolid in these indications has been reviewed and deemed appropriate to use at LTHT. Patients should be informed that other than in the above indications and including all usage in those less than 18 years of age that the medication is being used in for an off-label indication.

The maximum licensed treatment duration is 28 days.

Treatment courses of longer than 28 days in adults are off-label and should only be used on the recommended of microbiology or infectious diseases

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Therapeutic Drug Monitoring (checking levels)

Not required

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Pharmacokinetics2,5

Absorption
Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2 hours of dosing. Absolute oral bioavailability of linezolid (oral and intravenous dosing in a crossover study) is complete (approximately 100%). Absorption is not significantly affected by food.

Distribution
Volume of distribution is around 40-50 litres in healthy adults and approximates to total body water and is distributed into bone, fat, lungs, muscle, skin blister fluids and CSF.
Plasma protein binding is about 31% and is not concentration dependent.

Elimination
Linezolid is primarily excreted in the urine, with 50% of the changed metabolites found in the urine and 9% in the faeces. 30% of linezolid is found unchanged in the urine.
The elimination half-life of linezolid averages at about 5-7 hours.
Non-renal clearance accounts for approximately 65% of the total clearance of linezolid.

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Allergy advice

Contraindicated if hypersensitivity to linezolid or to any of the excipients.

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Key interactions (include BNF black dot)2,6

Interactions with other medicines
Due to the number of interactions with linezolid it is important that a full list of the patients current medication is provided as well as any medication stopped within the last month.

The manufacturers of linezolid state that unless there are facilities available for close observation and monitoring of blood pressure, linezolid should not be administered to patients on the following types of concomitant medications:

- Patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), directly and indirectly acting sympathomimetic agents (including the adrenergic bronchodilators, pseudoephedrine and phenylpropanolamine), vasopressive agents (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine), pethidine or buspirone.

This is due to the risk of serotonin syndrome and hypertensive crisis.

Therefore unless close observation and monitoring of blood pressure is available then any patient on the following medication should not receive linezolid.

Class

Examples

LTHT Guidance taken from SPC

Monoamine oxidase inhibitors (MAOI)

phenelzine
isocarboxazid tranylcypromine

Contraindicated. Increased risk of hypertension and CNS excitation (avoid concomitant usage and for at least 2 weeks after stopping the MAOI, RIMA and MAOB)

Reversible inhibitor of monoamine oxidase (RIMA)

moclobemide

Monoamine oxidase B inhibitors (MAOB)

rasagiline
selegiline

Selective serotonin re-uptake inhibitors (SSRI)

citalopram
escitalopram
fluoxetine
fluvoxamine
paroxetine
sertraline

Contraindicated due to risk of serotonin syndrome (see below)

Serotonin-noradrenaline re-uptake inhibitors (SNRI)

duloxetine
venlafaxine

Tricyclic antidepressants (TCA) and related

amitriptyline
clomipramine
dosulepin
doxepin
imipramine
lofepramine
nortriptyline trimipramine
mirtazepine

Opiates

pethidine

Contraindicated due to risk of hypertensive crisis and serotonin syndrome

Serotonin 5HT1 agonists

almotriptan
eletriptan
frovatriptan
naratriptan
rizatriptan
sumatriptan
zolmitriptan

Contraindicated due to risk of hypertensive crisis and CNS excitation (avoid concomitant usage and for at least 2 weeks after stopping the serotonin 5HT1 agonist)

Dopaminergic agents

dopamine, levodopa (without carbidopa/benserazide)

Caution due to risk of hypertensive crisis

**Note in those patients taking combination preparations with a dopa-decarboxylase inhibitor such as carbidopa and benserazide (eg. Sinemet and Madopar) the interaction is less likely to occur, but patients should be monitored for potential hypertensive crisis**

Direct and indirectly acting sympathomimetics

adrenaline dexamfetamine dextromethorphan (in cough mixtures) dobutamine
dopexamine
ephedrine
metaraminol
methylphenidate noradrenaline phenylephrine pseudoephedrine

Caution due to risk of hypertensive crisis. Patients should be told to avoid nasal decongestants and cough mixtures containing dextromethorphan and pseudoephedrine, whilst receiving treatment with linezolid.

Miscellaneous

bupropion

Contraindicated risk of hypertension and CNS excitation (avoid concomitant usage and for at least 2 weeks after stopping bupropion)


[THIS LIST IS NOT EXHAUSTIVE]

If patients are on any of the above medication then treatment with linezolid is not recommended. Microbiology/ Infectious diseases should be contacted for suitable alternatives and will recommend on best interest choices for patients.

Interactions where caution is required.

All other opiates (excluding pethidine)

Risks of CNS depression/ excitation and serotonin syndrome therefore advise to report any serotonin syndrome symptoms (see below).
Stopping and using suitable alternative to linezolid maybe required. Patients should be warned and told to seek medical attention if they experience any serotonin syndrome symptoms (see below).

Interactions with food and drink7,8
As linezolid is a reversible non-selective MAOI interaction with certain food that contains tyramine, causing a rise in blood pressure, can occur. Patients should be advised to avoid tyramine rich food (>100mg) including:

  • Mature or aged cheese
  • Fermented or air-dried meats such as salami
  • Yeast extracts such as Bovril, Oxo, Marmite
  • Fermented soya bean products such as soy sauce
  • Protein diet supplements
  • Sour cream and yoghurt
  • Beer and wine
  • Avocados and broad beans

Specialist Populations
Linezolid is also contraindicated in the following:

  • Uncontrolled hypertension (unless blood pressure monitoring is available)
  • Phaeochromocytoma,
  • Carcinoid
  • Thyrotoxicosis
  • Bipolar depression
  • Schizoaffective disorder
  • Acute confusional states
  • Bone marrow transplant patients

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Side effects and monitoring required2

Monitoring Summary

  • Full blood count (FBC, including haemoglobin levels, platelets, and total and differentiated leucocyte counts) WEEKLY for each week of treatment
  • Baseline visual acuity tests for when planning to give over 28 day’s treatment.

*See below for information about patients who may require closer monitoring

Side Effects

Myelosuppression
Myelosuppression (including anaemia, leukopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. The risk of these effects appears to be related to the duration of treatment.

All patients should have a weekly full blood count whilst receiving linezolid
Patients who may be at greater risk of experiencing blood dyscrasias and therefore may require closer monitoring include:

  • elderly patients
  • severe renal insufficiency
  • pre-existing anaemia,
  • granulocytopenia or thrombocytopenia;
  • are receiving concomitant medications that may decrease haemoglobin levels, depress blood counts or adversely affect platelet count or function;
  • Receive more than 14 days of therapy.

If significant myelosuppression occurs during linezolid therapy, treatment should be stopped unless it is considered absolutely necessary to continue therapy.

Information required on discharge advice note (eDAN) for patients discharged on linezolid

For the clinician responsible for writing the eDAN.
If your patient is a Leeds patient and is going to be discharged on >7 days of treatment with linezolid, they require weekly monitoring of their FBC.

  • Complete the OPAT linezolid monitoring referral form found via this link (LTHT Internal Only)
  • Print the FBC request forms to give to the patient or carer, who will visit their GP practice for their blood tests.
  • Consider contacting the GP via telephone to inform them that the patient will be attending their practice within the next week for a blood test.
  • The FBCs will be followed up by OPAT who will contact the consultant responsible for the patient’s care if there are any concerns with their results.

If your patient is not a Leeds patient and is going to be discharged on >7 days of treatment with linezolid, you will need to contact their GP to ensure they are happy to undertake the blood tests or make alternative arrangements for the patient to attend LTHT for their FBC monitoring.

For pharmacists validating the patient’s eDAN:
For Leeds patients, ensure that the OPAT linezolid referral form has been sent to the OPAT team and that the relevant number of FBC requests have been printed from ICE.
Please copy and paste the following wording in the ‘Actions for GP’ section of the eDAN:
This patient has been discharged on a course of linezolid and therefore requires a weekly full blood count (FBC) until the end of their prescribed course. Please obtain this on the following date(s) (xx/xx xx/xx). This has already been requested by the discharging doctor on ICE. LTHT take responsibility for reviewing these blood tests and will take necessary action if they are deranged.

For those who are not Leeds patients please ensure an appropriate plan has been put in place for the patient and this is documented in the ‘Actions for GP’ section of the eDAN.

Serotonin syndrome
Patients should be closely observed for signs and symptoms of serotonin syndrome such as;

  • Cognitive dysfunction,
  • Hyperpyrexia,
  • Hyperreflexia
  • Incoordination.

Spontaneous reports of serotonin syndrome associated with the co-administration of linezolid and serotonergic agents have been reported. Onset tends to be within the first few days, although some cases have reported delayed presentations up to 21 days.12.13
Patients where the risk of serotonin syndrome is higher ,those taking other serotonergic medication, should be monitored for signs of serotonin syndrome during the first 72 hours, but the risk of delayed presentation should also be taken into consideration12,13 (see interactions)
Co-administration of linezolid and serotonergic agents is therefore contraindicated.

Patients are still at risk of developing serotonin syndrome even if the antidepressant has been stopped. The washout period required ranges from 7 to 21 days; up to 6 weeks for fluoxetine, and is dependent on the antidepressant14. If a patient falls into this category then linezolid will also be contraindicated.

These cases should be discussed with microbiology/ infectious diseases to seek alternatives where linezolid is not appropriate due to interactions.

Peripheral and optic neuropathy
Peripheral neuropathy, as well as optic neuropathy and optic neuritis sometimes progressing to loss of vision, have been reported, these reports have primarily been in patients treated for longer than the maximum recommended duration of 28 days.
All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary. If any patients are taking linezolid for longer than the recommended 28 days, their visual function should be regularly monitored.

Lactic acidosis
Lactic acidosis has been reported with the use of linezolid. Patients who develop signs and symptoms of metabolic acidosis while receiving linezolid should receive immediate medical attention.
Continuation of the therapy should be based on a risk versus benefit assessment

Convulsions
Convulsions have been reported. In most of these cases, a history of seizures or risk factors for seizures was reported. Patients should be advised to inform their physician if they have a history of seizures.

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DRUG INDICATIONS
Prophylaxis indications in LTHT

Guideline for antimicrobial prophylaxis during invasive cardiology procedures in adults.
detail.aspx?id=2019

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Treatment indications in LTHT

Prevention and treatment of aspiration pneumonitis and aspiration pneumonia in adults

Guideline for the diagnosis and management of peritonitis in continuous and automated peritoneal dialysis patients

Management of acute parotitis in adults

Guideline for the management of breast abscesses and mastitis (breast cellulitis) in adults

Guideline for management of community-acquired rhinosinusitis (sinusitis) in adults

Cystic fibrosis in children and adults. The Leeds method of management.

Guideline for the management of infected parapneumonic effusions and empyema

Guidelines for the management of otitis externa in adults

Leeds Teaching Hospitals NHS Trust adult sepsis management guidelines 2016 (incorporating BUFALO)

Guideline for the management of cellulitis and necrotising fasciitis in adults

Clinical Guidelines for the Management of Adult Diabetic Foot Infections

Hospital Acquired Pneumonia (Non-ventilated Adult Patients)

Guideline for management of deep spinal infection in adults

Guideline for management of ventilator-associated pneumonia

Guideline for the management of endophthalmitis (post-operative, post trauma, bleb-related, endogenous) and penetrating eye injuries

The Management of Staphylococcus aureus (S.aureus) on a respiratory sample from a patient with cystic fibrosis

Treatment of Mycobacterium Abscessus Respiratory Tract infections in Children and Adults with Cystic Fibrosis

Diagnosis and Management of CSF Shunt Infections in Adults

Community Acquired Pneumonia

Guideline for the management of Acute Otitis Media and Mastoiditis in Adults

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Prescribing restriction

Linezolid should only be initiated in a hospital environment and is classed as a red drug at LTHT. All monitoring, including post discharge should be undertaken by the patient’s own consultant.

Each guideline that recommends linezolid has been approved by a microbiologist or infectious diseases specialist for that particular indication and so can be used without a microbiology authorisation code.

For all other uses linezolid should only be initiated after consultation with a microbiologist or infectious diseases consultant. A microbiology authorisation code will be required
Due to the number of interactions with linezolid it is important that a full list of the patients current medication is provided as well as any medication stopped within the last month.

Provenance

Record: 5155
Objective:
Clinical condition:
Target patient group:
Target professional group(s): Secondary Care Doctors
Pharmacists
Adapted from:

Evidence base

References

  1. BNF https://www.medicinescomplete.com/mc/bnf/current/PHP3551-linezolid.htm?q=linezolid&t=search&ss=text&tot=15&p=1#_hit. (Accessed 27th June 2017)
  2. EMC. https://www.medicines.org.uk/emc/medicine/31359. Summary of Product Characteristics. Linezolid 2mg/ml solution for infusion. Date of revision of text 12th May 2017. Pfizer Limited. http://www.medicines.org.uk/emc/medicine/17779/spc Assessed 15th March 2017.
  3. Ashley C, Dunleavy A. Renal Drug Database - Linezolid. 2017. Available from https://renaldrugdatabase.com/. Accessed 20/06/2017
  4. BNFc https://www.medicinescomplete.com/mc/bnfc/current/PHP3551-linezolid.htm?q=linezolid&t=search&ss=text&tot=15&p=1#_hit (Accessed 27th June 2017)
  5. Brayfield, A. (Ed.). Martindale: the complete drug reference. 2017. Available from http://www.medicines-complete.com
  6. Preston, L. C. (Ed.). Stockley’s drug interactions.2017. Available from http://www.medicines-complete.com
  7. Rumore M.M and Roth. M. Dietary Tyramine Restriction for Hospitalized Patients on Linezolid: An Update. Nutrition in Clinical Practice. 2010; 25(3): 265- 269. Available from https://www.ncbi.nlm.nih.gov/pubmed/20581320 (Accessed 15th March 2017)
  8. Fiedorowicz J.G. and Swartz, K.L. The Role of Monoamine Oxidase Inhibitors in Current Psychiatric Practice. The Journal of Psychiatric Practice. 2004; 10(4) : Pp. 239-248. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2075358/pdf/nihms31302.pdf. (Accessed 15th March 2017).
  9. EMC. https://www.medicines.org.uk/emc/medicine/30319 Summary of Product Characteristics. Sivextro. Date of revision of text 20th December 2016. Merck Sharp & Dohme.
  10. Rybak, JM and Roberts K. Tedizolid Phospahte: A Next Generation Oxazolidinone. Infectious Diseases and Therapy. 2015; 4: Pp. 1-14. Available from: https://link.springer.com/content/pdf/10.1007%2Fs40121-015-0060-3.pdf . (Accessed 27th June 2017)
  11. Lodise TP, Bidell MR, Flanagan SD, Zasowski EJ, Minassian Sl and Prokocimer P. Characterization of the haematological profile of 21 days of tedixolid in healthy patients. The Jounral of antimicrobial chemotherapy. 2016, 71 (9): Pp. 2553-2558. Availabe from: https://academic.oup.com/jac/article/71/9/2553/2238771/Characterization-of-the-haematological-profile-of . (Accessed 27th June 2017)
  12. Woytowish, M.R and Maynor L.M. Clinical Relevance of Linezolid-Associated Serotonin Toxicity. The Annals of Pharmacotherapy. 2013; 47: 388- 397. Available from: http://journals.sagepub.com/home/aop. (Accessed 15th March 2017).
  13. Kuczynska, J. South West Medicines Information and Training. Q&A 192.5. What is the risk of interaction between opioids and monoamine oxidase inhibitors (MAOIs)? Available from: https://www.sps.nhs.uk/wp-content/uploads/2016/09/SW-QA192.5-Opiates-MAOIs-final.doc. Accessed 02/05/2017
  14. Henderson S. North West Medicines Information Centre. Q&A 151.5 How do you switch between monoamine oxidase inhibitors and SSRI, tricyclic or related antidepressants? November 2015. Available from https://www.sps.nhs.uk/wp-content/uploads/2015/12/NW-QA151.5-How-do-you-switch-between-MAOIs-and-SSRIs-TCAs-or-related-antidepressants-.pdf . Accessed 02/05/2017.
  15. J. Southampton Medicines Advice Service. Q&A 219.4. What is serotonin syndrome and which medicines cause it? Available from: https://www.sps.nhs.uk/wp-content/uploads/2016/12/QA219_4_WhatisSerotoninSyndrome.doc. Accessed 02/05/2017

Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 1.0

Related information

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