Department of Microbiology Antimicrobial Prescribing Guidelines

Vancomycin - Prescribing guidance for Adults

• Drug information
• Introduction
• Antimicrobial activity
• Doses/routes of administration
• Therapeutic drug monitoring (checking levels)
• Pharmacokinetics
• Allergy advice
• Key interations
• Side effects and monitoring required
• Prescribing restriction

This document provides guidelines for secondary care doctors, secondary care nurses, and pharmacists regarding the situations in which it would be appropriate to consider the use of Vancomycin . This document is supplementary to, and should be used in conjunction with, the summary of product characteristics. Please contact the duty microbiologist or pharmacy infection team if further information is required.

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

Vancomycin is a glycopeptide antibiotic that has bactericidal activity against aerobic and anaerobic Gram-positive bacteria including multi-resistant staphylococci. However, there are reports of Staphylococcus aureus with reduced susceptibility to glycopeptides. There are increasing reports of glycopeptide-resistant enterococci. Penetration into cerebrospinal fluid is poor.¹

The primary mode of action of Vancomycin is inhibition of cell wall synthesis. In addition, Vancomycin may alter bacterial cell membrane permeability and RNA synthesis.²

Vancomycin works most effectively when the levels of the drug remain above the minimum inhibitory concentration (MIC) for the target organism(s) at all times.

MICs for organisms such as MRSA, CoNS, and enterococci are typically around 1mg/L. Hence a trough serum vancomycin level above 10mg/L would imply that continuous levels above the MIC are being achieved, certainly for bloodstream infections.³

For other infections, e.g. pneumonia the exact levels at the site of infection will be unknown. However, it is reasonable to assume that the higher the trough serum level, the greater the likelihood that the level in extravascular sites of infection is going to be above the MIC. Therefore, for some deep tissue infections (e.g. osteomyelitis, endocarditis), you may be advised to maintain trough serum levels at the higher end of the normal range.

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• Staphylococcus aureus including meticillin-resistant Staphylococcus aureus (MRSA)
• Streptococci and enterococci (vancomycin resistant enterococci are occasionally encountered in Leeds)
• Clostridium difficile
• Other Multi-resistant Gram-positive organisms, or coagulase-negative staphylococci (CoNS), and amoxicillin resistant enterococci.

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Vancomycin can be administered intravenously by intermittent or continuous infusion, it can also be given orally, intrathecally, intraperitoneal, intravitreal and intracameral depending on the clinical indication.

1. Intermittent intravenous infusion

1. Give an initial loading dose based on the patient’s actual body weight (table 1).
2. Calculate the initial maintenance dose based on the patient’s creatinine clearance using the vancomycin calculator (table 2). These are designed to achieve trough levels of 10 to15mg/L.
3. Give the 1st maintenance dose after the dosing interval specified in table 2.
4. Monitor pre-dose (trough) level at 36 to 48 hours table 2
5. Adjust maintenance dose according to current dosing regime and guidance in table 3

2. Continuous intravenous vancomycin infusion

Some specialist units use a continuous Vancomycin infusion – see local policy

3. Oral vancomycin

125mg orally 6 hourly (see Clostridium difficile treatment guideline)

4. Intrathecal vancomycin

20mg OD. The dose may be split and given in both external ventricular drains (EVDs) in non-communicating ventricles.

5. Line lock vancomycin therapy

10mg in 2ml for central venous catheters

6. Intraperitoneal (IP)

An initial dose of 2g (or 1.5g if <45kg body weight) is administered IP in a long dwell (in 2 litres dialysate for minimum of 6 hours, though this volume may be lower if 2 litre dwells not tolerated).

7. Intracameral and Intravitreal

1mg in 0.1ml

DOSE ADJUSTMENT IN RENAL IMPAIRMENT/FAILURE

Use table 2 to calculate dose for patients with renal impairment

Haemodialysis and renal replacement therapy – see local guideline

DOSE IN OBESITY

Use the vancomycin calculator to calculate the dose for patients who are obese (BMI>40).

DOSE IN LIVER FAILURE

There is no dose adjustment required.

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1. Intravenous infusion

When to assay

• Monitor trough (pre-dose) level only: i.e. not a post dose
• If a previous result has been too high, and /or satisfactory drug clearance is required: a “random” assay is sent
• If on a continuous infusion regime: refer to protocol
• The next dose should be given before receiving the result

Normal therapeutic range:

• Trough levels between 10-20 mg/L
• Trough levels should be maintained above 10mg/L to avoid resistance
• For MRSA pneumonia, osteomyelitis, endocarditis & bacteraemia, trough levels of 15 to 20mg/L are recommended to improve penetration, increase the probability of optimal target serum concentrations, and improve clinical outcomes

Specific response to a vancomycin assay result:

Always interpret the result in the light of the patient’s clinical condition and available culture and sensitivity results.

• Trough level in the normal range (10-20mg/L):
  • Ensure the patient is responding clinically. If satisfactory, no change is indicated. If clinical response is not satisfactory, it could indicate a higher dose is required or that additional therapy needs to be introduced alongside or instead of Vancomycin . Please discuss with the duty microbiologist if further guidance required on a case-by-case basis. See dosing table 3
• Trough level too high (>20mg/L) see dosing table 3
  • Check when the assay was taken in relation to the Vancomycin dose – high levels can result from levels being taken during or shortly after an infusion (i.e. they are not true trough levels)
  • Check where the blood sample was taken from – falsely high levels can be obtained from samples taken from the same line that the drug was infused through
  • Check the patient’s renal function. An increase in trough level may coincide with decreased creatinine clearance
  • If the high trough level appears genuine, consider reducing the dose frequency &/or unit dose. Omission may be appropriate until a satisfactory random assay result has been obtained. See dosing table 3
• Trough level too low (<10mg/L) see dosing table 3
  • Check to ensure that previous dose(s) have been given as prescribed
  • If the low trough level appears genuine, consider increasing the dose and/or the dose frequency if clinically appropriate. See dosing table 3

Contact pharmacy if required for advice on dose adjustments. If a patient requires a dose above 1.5g twice daily, please contact the Pharmacy Infection Team (Monday to Friday) for advice, or the on-call pharmacist if out-of-hours.

Frequency of testing:

• Trough levels should normally be checked after 36 to 48 hours of therapy. This should also be the case after any dose adjustment. See table 2 for information on when to take first vancomycin trough level
• Repeat daily level for haemodynamically unstable patients; after 48hours for a change of dose; and after 7 days if dose remains the same
• In patients with unstable renal function and/or uncertain clinical response, testing may need to be more frequent

2. Intraperitoneal

• Blood Vancomycin
  levels must be checked every 3 days. Further doses (same as initial dose based) should be given at 3 day intervals if indicated according to blood levels (see below) until the end of course.
• Clearance of Vancomycin
  after single IP loading dose varies with differing residual function. Maintenance of therapeutic blood levels is crucial for successful eradication of infection.

Vancomycin level

• >20mg/L
  Do not give Vancomycin and repeat blood test in a further 3 days
• <20mg/L Give Vancomycin
  2g IP (or 1.5g if <45kg body weight) as before and repeat blood test in a further 3 days

3. Oral, intrathecal, line lock therapy, intracameral, intravitreal

No therapeutic drug monitoring is required.

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Absorption: Vancomycin is not significantly absorbed from the normal gastro-intestinal tract and is therefore not effective by the oral route for infections other than staphylococcal enterocolitis and pseudomembranous colitis due to Clostridium difficile.

Distribution: After IV administration of vancomycin hydrochloride, inhibitory concentrations are present in pleural, pericardial, ascitic, atrial appendage tissue and synovial fluid, as well as urine and peritoneal fluid. Vancomycin does not readily penetrate the cerebrospinal fluid unless the meninges are inflamed.

Excretion/metabolism: About 75% of an administered dose of Vancomycin is excreted in urine by glomerular filtration in the first 24 hours. Renal dysfunction slows excretion of vancomycin. There is no apparent metabolism of the drug.

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Hypersensitivity to the active substance or to any of the excipients. Vancomycin should be administered with caution in patients allergic to teicoplanin, since allergic cross reactions between Vancomycin and teicoplanin have been reported.

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Increased risk of nephrotoxicity and ototoxicity when Vancomycin is given with:

• aminoglycosides
• ciclosporin
• loop diuretics
• amphotericin B
• bacitracin and polymixin B
• colistin
• cisplatin

If they need to be given, daily monitoring of renal function is required

• suxamethonium - Vancomycin enhances effects of suxamethonium
• anaesthetic agents - Concomitant administration of Vancomycin and anaesthetic agents has been associated with erythema, histamine-like flushing and anaphylactoid reactions

[THIS LIST IS NOT EXHAUSTIVE]

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Side effects

• Contrary to popular perception there is actually very little evidence of dose-associated nephrotoxicity with Vancomycin . Hence the risk of trough levels >20 mg/l is uncertain
• Vancomycin can act to potentiate the nephrotoxocity of other drugs if given in combination e.g. with aminoglycosides
• There has been some suggestion that very high levels of Vancomycin (e.g. >80 mg/l) may be ototoxic but this remains unproven
• Hypersensitivity reactions, rashes (including exfoliative dermatitis), anaphylaxis, and drug fever. Vancomycin has been associated with the bullous eruption disorders, Stevens-Johnson syndrome, toxic epidermal necrolysis and linear IgA bullous dermatosis. If a bullous disorder is suspected, the drug should be discontinued and specialist dermatological assessment should be carried out
• During or soon after rapid infusion of Vancomycin , patients may develop anaphylactoid reactions including hypotension, wheezing, dyspnoea, urticaria or pruritus. Rapid infusion may also cause flushing of the upper body (red neck syndrome) or pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours. Such events are infrequent if Vancomycin is given by slow infusion over 60 minutes. In studies of normal volunteers, infusion-related events did not occur when Vancomycin was administered at a rate of 10mg/min or less.

Monitoring

• Daily serum creatinine & urea is recommended for patients on IV vancomycin
• Nephrotoxicity - a minimum of 2 to 3 documented increases in serum creatinine of >50% or >45mmol/L rise from baseline after several days of vancomycin. contact microbiology or pharmacy if this occurs. It may not be due to the vancomycin
• Monitor FBC regularly as neutropenia or thrombocytopenia can occur after prolonged therapy

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