Therapeutic Drug Monitoring and penicillin allergy Duty of

Therapeutic Drug Monitoring and penicillin allergy (Duty of care with toxic drugs) Dr Kieran Hand Consultant Pharmacist, Anti-infectives SUHT, November 2007

Why monitor drug levels? • • • Optimise dose regimen for individual patient Explain lack of efficacy Prevent / confirm toxicity Evaluate impact of drug interactions Evaluate impact of low albumin Evaluate impact of changes in organ function or fluid status • Check patient compliance

Drugs routinely monitored • Anti-epileptics – Phenytoin, Carbamazepine, (Valproate) • Antibiotics – Gentamicin, Tobramycin – Vancomycin, Teicoplanin • Anti-psychotics – Lithium • Cardiac glycosides – Digoxin • Bronchodilators – Aminophylline – Theophylline • Specialty drugs

e. Quest screen - Lithium

e. Quest screen - search

e. Quest screen - antibiotics

Narrow therapeutic index

When to sample – steady state

The effect of loading dose – immediate efficacy

Blood sampling and the distribution phase

Anti-epileptics

Phenytoin Half-life 22 hours but caution: saturable metabolism Time to steady state sampling Varies considerably between patients (1 -5 weeks) Loading dose 18 mg/kg slow iv infusion for status epilepticus over 30 -60 mins (ECG recommended) Maintenance dose 100 mg 6 -8 hourly iv (convert to od if stable) 200 -500 mg once daily po When to take blood Pre-dose How often to repeat Sample within 2 -3 days of initiation then again 3 -5 days later. If no change, monitor weekly. Sampling method Li-heparin/SST Signs of toxicity Far-lateral nystagmus, diplopia, ataxia, confusion, slurred speech, hyperglycaemia, respiratory/circulatory depression (2 -5 g lethal) Target range 10 -20 mg/L (bound + free drug); Note: high protein binding Practical issues 100 mg iv = 100 mg tablet = 90 mg liquid

Phenytoin accumulation

Phenytoin – key points • Saturable metabolism so increase dose carefully • Long half-life (1 day) so pointless to sample blood before one week if initiating oral therapy • Serum levels must be adjusted for abnormal albumin concentration – call a pharmacist (low albumin leads to plasma phenytoin level appearing low but tissue levels normal) • Susceptible to protein binding displacement (plasma level appears low but tissue levels normal) • Susceptible to liver enzyme inhibition and induction

Carbamazapine Half-life 30 hr then 15 hr due to autoinduction Time to steady state sampling 5 -7 days after dose change Loading dose Slow titration: 100 -200 mg bd oral > increasing by 100 -200 mg each week Maintenance dose 200 -800 mg bd When to take blood Pre-dose How often to repeat After dose changes (5 -7 days) Sampling method Li-heparin/SST Signs of toxicity Vomiting, CNS disturbances, tachycardia, haemodynamic instability, respiratory depression, coma Target range 4 -12 mg/L

Carbamazepine – key points • Autoinduces it’s own metabolism (one month) • Wider therapeutic index than phenytoin • Susceptible to liver enzyme induction or inhibition • Induces increased metabolism of other drugs

Antibiotics

Concentration Gentamicin extended interval dosing Time

Reduced elimination Concentration MTC MEC Time

Reduced elimination Concentration MTC MEC Time

Gentamicin Half-life 2 -3 hours Time to steady state sampling 6 -14 hours post 1 st dose sampling window for 5 mg/kg regimen Before and after 3 rd dose for 8 -hourly dosing Loading dose Not applicable Maintenance dose 5 mg/kg every 24, 36 or 72 hours or 1 mg/kg every 8 -12 hours When to take blood 6 -14 hours post-dose for 5 mg/kg dosing regimen Pre-dose for trough 1 hour after start of infusion for peak (distribution phase) How often to repeat Twice weekly if renal function and fluid status stable Sampling method Plain tube (clotted blood - red top) Signs of toxicity Nephrotoxicity and renal failure, ototoxicity (vestibular damage or hearing loss) Target range High-dose regimen – see nomogram 8 -hourly regimen – peak 5 -10 mg/L, trough <1. 0 mg/L for Gram –ve sepsis

Gentamicin – key points • Gentamicin causes permanent renal failure if levels are kept above 1 mg/L for a prolonged period of time • High-dose regimen (5 mg/kg) equally effective as traditional dosing • High-dose regimen no more toxic than traditional dosing • See SUHTranet for exclusion criteria

Vancomycin Half-life 6 -7 hours Time to steady state sampling Pre-dose at 3 rd or 4 th dose Loading dose 1 -1. 5 grams Maintenance dose 1. 5 grams bd (see intermittent dosing guideline) When to take blood Pre-dose How often to repeat Every 3 days if renal function stable Sampling method Plain tube (clotted blood - red top) Signs of toxicity Rapid infusion causes ‘Red Man Syndrome’ Nephrotoxicity and renal failure; Ototoxicity with hearling loss, vertigo, dizziness, tinnitus Target range 10 -15 mg/L (once daily or twice daily dosing) 20 -25 mg/L continuous infusion

Vancomycin – key points • Activity related to time levels are above MIC for target pathogen • Vancomycin is rarely nephrotoxic if monitored carefully • Nephrotoxicity is usually associated with concurrent prescribing of other nephrotoxic drugs • ICU uses continuous infusion vancomycin

Teicoplanin Half-life ONE WEEK Time to steady state ONE MONTH Loading dose 400 mg 12 -hourly for 3 doses is ESSENTIAL Maintenance dose 400 -600 mg daily (at least 6 mg/kg) When to take blood Pre-dose How often to repeat Monthly Sampling method Plain tube (clotted blood - red top) Signs of toxicity Renal failure, hearing loss, vestibular disorder, tinnitus Target range Trough >10 mg/L (>20 mg/L for IE) Peak 20 -50 mg/L

Teicoplanin – key points • Inferior efficacy to vancomycin • Frequently underdosed – associated with treatment failure • Levels sent off to Bristol - delay • Advantage of once-daily dosing • Reduce dose on 4 th day if renal impairment • Less nephrotoxic than vancomycin • Expensive

Cardiac glycosides

Digoxin Half-life 30 -40 hours Time to steady state sampling >1 week Loading dose IV 10 microgram/kg in 100 m. L saline over 2 hr oral 15 microgram/kg (750 -1, 500 micrograms in divided doses) Maintenance dose 62. 5 micrograms – 250 micrograms once daily When to take blood Pre-dose preferably (at least 6 hours after oral dose to allow distribution) How often to repeat 1 week after initiation or dose change Sampling method Li-heparin/SST Signs of toxicity Anorexia, nausea, vomiting, various arrhythmias, atrial tachycardia, 10 -15 mg fatal in adults, Target range 1 -2 microgram/L Practical issues 125 mcg tablet 100 mcg liquid (2 m. L) 80 mcg iv

Digoxin - key points • Low potassium potentiates risk of arrhythmias • Maintenance dose usually guesstimated from weight and renal function • Pharmacist can provide more accurate estimate • Clinically significant interaction with amiodarone • Digibind® reduces mortality in overdose but phenytoin is a cheaper alternative in mild cases

Antipsychotics

Lithium Half-life 24 hours Time to steady state sampling 4 -5 days after starting or change in therapy or sodium/fluid intake Loading dose 400 mg-1. 2 g daily Maintenance dose 400 mg – 1, 200 mg od po When to take blood pre-dose How often to repeat Weekly until dose stable then at least 3 -monthly Sampling method Plain tube Signs of toxicity Hyperreflexia & hyperextension of limbs, convulsions, psychoses, syncope, renal failure, circulatory failure, coma, death Target range 0. 4 – 1. 0 mmol/L Practical issues Slow release brands not interchangeable

Lithium – key points • Renal excretion – 100% filtered but 80% reabsorbed – Li+ reabsorption linked to Na+ reabsorption – Influenced by dehydration, sodium depletion, hypotension – Diuretics (e. g. thiazides) can increase Lithium levels dramatically • NSAIDs and ACEi’s can increase Li+ levels toxicity

Bronchodilators

Theophylline /Aminophylline iv Half-life 8 hours Time to steady state sampling 2 hours post load, then 12 hours into infusion Oral: 5 days after starting Loading dose 5 mg/kg iv if treatment naïve in 100 m. L over 20 mins Maintenance dose Infusion 0. 5 mg/kg/hour (500 mg in 500 m. L) Oral: 200 -500 mg 12 -hourly (slow release) When to take blood 24 hours into infusion Oral – pre-dose (at least 4 -6 hours post-dose) How often to repeat As required Sampling method Li-heparin/SST Signs of toxicity Nausea, vomiting and haematemesis, agitation, restlessness, dilated pupils and convulsions, hypotension and life-threatening cardiac arrhythmias Target range 10 -20 mg/L Practical issues Slow release brands not interchangeable Theophylline 790 mg = Aminophylline 1, 000 mg

Theophylline / aminophylline key points • Theophylline concentration is increased in – Heart failure – Cirrhosis – Elderly – Liver enzyme inhibitors • Theophylline concentration is decreased by – Smoking – Social drinking – Liver enzyme inducers

Specialty drugs for monitoring – seek expert advice • Immunosuppressants – Ciclosporin / Tacrolimus / Sirolimus – Methotrexate • Anti-epileptics – Valproate – Phenobarbitol – Ethosuximide • Tricyclic antidepressants – Amitriptyline, nortriptyline, imipramine etc

Important concepts • • • You prescribe a toxic drug – you monitor it Seek advice from the ward pharmacist or Medicines Info Loading dose for drugs with long half-life Distribution phase (when to sample blood after dose given) Documenting sampling times Steady state (when to check levels after start of therapy or change to therapy) • Actions: reducing dose or extending dosing interval • Slow-release brands are not easily interchangeable • Many TDM drugs are susceptible to serious drug interactions – caution if starting/stopping other drugs and check with pharmacist or BNF

Penicillin allergy • Megan, 19 -years-old, student • PC ‘Serious infection’ • Allergies ‘Penicillin – itchy rash and lips swollen’ • Rate the following antibiotics as: – Safe – Caution – perform risk assessment – Danger

Penicillin allergy • • Clindamycin Amoxicillin Moxifloxacin Daptomycin Doxycycline Tazocin Azithromycin Gentamicin • • Metronidazole Ceftriaxone Vancomycin Flucloxacillin Meropenem Cefuroxime Augmentin Rifampicin

Penicillin allergy • • Clindamycin Amoxicillin Moxifloxacin Daptomycin Doxycycline Tazocin Azithromycin Gentamicin • • Metronidazole Ceftriaxone Vancomycin Flucloxacillin Meropenem Cefuroxime Augmentin Rifampicin

Facts about penicillin allergy • 10 -20% of patients reporting a penicillin allergy are truly allergic (Salkind 2001 JAMA) • Frequency of all ADRs to penicillin in general population is 0. 7 -10% • Anaphylaxis occurs in between 1: 6, 500 and 1: 25, 000 penicillin courses • History of atopy is not predictive of penicillin anaphylaxis but may severity • Patients on beta-blockers may be at increased risk of death if anaphylaxis occurs • Understanding the classification of penicillin hypersensitivity reactions helps with risk assessment

Gell and Coombs Classification Time of Mediator onset after exposure Type I (immediate) < 1 hour after exposure Clinical signs Skin Comments testing useful Anaphylaxis and/or Yes Penicillinspecific Ig. E laryngeal oedema, wheezing / antibodies bronchospasm, angioedema, urticaria/pruritis, diffuse erythema IV > oral Fatal in 1: 50, 000100, 000 treatment courses Some Ig. E reactions occur from 1 -72 hours post exposure Late reactions > 72 hours after exposure Type II >72 hours Ig. G, complement red blood cells, platelets No Type III >72 hours Ig. G, Ig. M immune complexes Serum sickness, No tissue injury Type IV >72 hours Contact dermatitis Other (idiopathic) Usually Unknown >72 hours clearance by lymphoreticular system Tissue lodging of immune complexes, drug fever No Maculopapular or No morbilliform rashes 1 -4% of all patients receiving penicillin 3. 5% on rechallenge

Taking a History of Penicillin Allergy: What to Ask • What was the patient’s age at the time of the reaction? Type I reactions most common in 20 -50 year olds • Does the patient recall the reaction? If not, who informed them of it? How reliable is the history? • How long after beginning penicillin did the reaction begin? If onset >3 days after exposure then unlikely to be Type I reaction. • What were the characteristics of the reaction? If a detailed history of a patient’s reaction to penicillin indicates that the rash was strictly maculopapular, with no signs of a type I reaction, then it appears to be safe to readminister an antibiotic that contains penicillin. • What was the route of administration? Type I reactions much more likely with parenteral administration • Why was the patient taking penicillin? Drug-independent rashes are common in patients with viral infections and infections with numerous bacteria can also be associated with a rash. • What other medications was the patient taking? Why and when were they prescribed? Did the reaction coincide with administration of other medications known to cause allergy? • What happened when the penicillin was discontinued? A positive dechallenge increases the likelihood of a true penicillin reaction • Has the patient taken antibiotics similar to penicillin (for example, amoxicillin, ampicillin, cephalosporins) before or after the reaction? If yes, what was the result? Cross-reactivity to cephalosporins and carbapenems is up to 10% for patients with Type I reaction to penicillins (avoid)

Questions?