Department of Microbiology (Restricted) Antimicrobial Prescribing Guidelines

Linezolid

• Drug information
• Introduction
• Antimicrobial activity
• Dose/Routes of administration
• Therapeutic drug monitoring (checking levels)
• Pharmacokinetics
• Allergy advice
• Key interactions (include BNF black dot)
• Side effects and monitoring required
• Drug indications
• Prophylaxis indications in LTHT
• Treatment indications in LTHT
• Prescribing restriction

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.

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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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

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/FAILURE^1,2,3
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 DOSES^2,4
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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Not required

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

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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.

[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.

Interactions with food and drink^7,8
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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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 consideration^12,13 (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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Guideline for antimicrobial prophylaxis during invasive cardiology procedures in adults.
http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?id=2019

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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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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.