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?
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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
eQuest screen - Lithium
eQuest screen - search
eQuest 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
18mg/kg slow iv infusion for status epilepticus over
30-60mins (ECG recommended)
Maintenance dose
100mg 6-8 hourly iv (convert to od if stable)
200-500mg 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 (2-5g lethal)
Target range
10-20mg/L (bound + free drug); Note: high protein
binding
Practical issues
100mg iv = 100mg tablet = 90mg 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
30hr then 15hr due to autoinduction
Time to steady state sampling
5-7 days after dose change
Loading dose
Slow titration: 100-200mg bd oral >
increasing by 100-200mg each week
Maintenance dose
200-800mg 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
4-12mg/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 1st dose sampling window for 5mg/kg regimen
Before and after 3rd dose for 8-hourly dosing
Loading dose
Not applicable
Maintenance dose
5mg/kg every 24, 36 or 72 hours or
1mg/kg every 8-12 hours
When to take blood
6-14 hours post-dose for 5mg/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 5-10mg/L, trough <1.0mg/L for
Gram –ve sepsis
Gentamicin – key points
• Gentamicin causes permanent renal failure
if levels are kept above 1mg/L for a
prolonged period of time
• High-dose regimen (5mg/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 3rd or 4th 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
10-15mg/L (once daily or twice daily dosing)
20-25mg/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
400mg 12-hourly for 3 doses is
ESSENTIAL
Maintenance dose
400-600mg daily (at least 6mg/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 >10mg/L (>20mg/L for IE)
Peak 20-50mg/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 4th 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 100mL saline over 2hr
oral 15 microgram/kg (750-1,500 micrograms in
divided doses)
Maintenance dose
62.5micrograms – 250micrograms 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, 10-15mg fatal in adults,
Target range
1-2 microgram/L
Practical issues
125mcg tablet  100mcg liquid (2mL)  80mcg 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
400mg-1.2g daily
Maintenance dose
400mg – 1,200mg 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
5mg/kg iv if treatment naïve in 100mL over 20 mins
Maintenance dose
Infusion 0.5mg/kg/hour (500mg in 500mL)
Oral: 200-500mg 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
10-20mg/L
Practical issues
Slow release brands not interchangeable
Theophylline 790 mg = Aminophylline 1,000mg
Theophylline / aminophylline
key points
• Theophylline concentration is increased in
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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
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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
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Clindamycin
Amoxicillin
Moxifloxacin
Daptomycin
Doxycycline
Tazocin
Azithromycin
Gentamicin
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Metronidazole
Ceftriaxone
Vancomycin
Flucloxacillin
Meropenem
Cefuroxime
Augmentin
Rifampicin
Penicillin allergy
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Clindamycin
Amoxicillin
Moxifloxacin
Daptomycin
Doxycycline
Tazocin
Azithromycin
Gentamicin
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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
Clinical signs
Skin
Comments
testing
useful
Type I
(immediate)
< 1 hour
after
exposure
Anaphylaxis
and/or laryngeal
oedema, wheezing
/ bronchospasm,
angioedema,
urticaria/pruritis,
diffuse erythema
Yes
IV > oral
Fatal in 1:50,000100,000 treatment
courses
Some IgE reactions
occur from 1-72
hours post exposure
 red blood cells,
 platelets
No
 clearance by
lymphoreticular
system
Type III >72 hours IgG, IgM
immune
complexes
Serum sickness,
tissue injury
No
Tissue lodging of
immune complexes,
drug fever
Type IV >72 hours
Contact dermatitis
No
Maculopapular or
morbilliform
rashes
No
Penicillinspecific IgE
antibodies
Late reactions > 72 hours after exposure
Type II >72 hours IgG,
complement
Other
(idiopathic)
Usually
Unknown
>72 hours
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 >3days 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?