Indication Avoid toxicity (trough) and efficacy (peak) How it is done Take a peak and trough level before the third dose or on day 2 Target The trough level should be <2 mg/mL. The peak should be 4–8 mg/mL Interpretation

If the trough level is >2 mg/mL, withhold the next doses until the level falls to <2 mg/mL

Adjust the dosage interval rather than the actual dose

If the peak is too low consult a pharmacist or microbiologist for advice

Once-daily dosing

7 mg/kg IV

If obese, do not use their actual weight, but calculate their corrected body weight

Contraindication Once-daily dosing is not appropriate for a CrCl <20 mL/minute, oliguria, haemofiltration, endocarditis, severe liver disease, cystic fibrosis, major burns, prophylaxis or infants <6 months Indication For safe and effective therapy How it is done Levels any time between 6 and 14 hours postdose Interpretation

Refer to the Hartford nomogram (Fig. 10.1)

If the levels are high, increase the interval between doses as per the Hartford nomogram

Fig. 10.1 Hartford nomogram for gentamicin once-daily dosing regimen.

For obese patients, use corrected body weight:

• Ideal body weight (IBW) in kilograms:

–IBW (male) = 50 kg in weight + (2.3 × every inch over 5 ft in height)

–IBW (female) = 45 kg in weight + (2.3 × every inch over 5 ft in height)

• Excess body weight (EBW):

• Corrected body weight (CBW):

Use if patient is >15% obese.

Digoxin

See Table 10.2 for the dosing regimen, and Box 10.1 for drugs that can increase or reduce levels of the drug.

Table 10.2 Digoxin dosing regimen

Loading dose

Urgent: 750 μg to 1 mg IV over 2 hours or 1–1.5 mg PO over 24 hours in divided doses (6-hourly loading allows for distribution and less nausea)

Less urgent: 250–500 μg PO daily for 3 days

Maintenance dose

125–250 μg PO OD

Less in the elderly or the renally impaired

Indication

Avoid toxicity

Investigate treatment failure

How it is done

Take levels 1 week after starting treatment

Sample 6–9 hours postdose, or immediately predose

Not necessary in all patients starting therapy. Advisable in the elderly and the renally impaired

Interpretation

Recommended therapeutic range:

• 0.5–0.8 μg/L (0.6–1 nanomol/L) target in heart failure

• 1.5–2 μg/L (1.9–2.6 nanomol/L) target in arrhythmias

>3 μg/L (3.8 nanomol/L) is usually associated with signs of toxicity

Toxicity possible at levels as low as 1.5 μg/L (1.9 nanomol/L)

Action Patient toxic and levels raised:

• If life-threatening, i.e. level >4 μg/L (5.1 µmol/L), omit drug, treat with Digibind (expensive)

• Determine cause before restarting

• If restarting, consider a lower dose. In general, to achieve a serum concentration of half the value, reduce the maintenance dose by half

Patient toxic but levels within therapeutic range:

• Exclude other causes of toxic symptoms

• Check K⁺

• Reduce dose, consider additional therapy for cardiac failure of arrhythmia

Patient clinically undertreated, and levels low:

• Increase dose, usually by 50–75 μg daily, and recheck levels

Patient clinically undertreated, but levels within therapeutic range:

• Consider additional therapy

Important Hypokalaemia and hypothyroidism are commonly associated with digoxin toxicity, so in suspected toxicity check K⁺ and thyroid function!

Box 10.1 Drugs that affect digoxin levels in the body

Can increase levels	Can reduce levels
Amiodarone Bendroflumethiazide Ciclosporin Diltiazem Furosemide Itraconazole Macrolides Propafenone Quinidine Spironolactone Telmisartan Verapamil

Antacids

Cholestyramine

St John’s Wort

Phenytoin

See Table 10.3 for the dosing regimen, and Box 10.2 for drugs that can increase or reduce levels of the drug.

Table 10.3 Phenytoin dosing regimen

Loading dose	15 mg/kg IV: maximum rate of 50 mg/minute
Maintenance dose	100 mg IV 6- to 8-hourly 150–300 mg PO OD. Gradually increasing to 200–500 mg PO OD Doses can be split if not tolerated

Indication

Ensure achieving therapeutic target

Avoid toxicity

Narrow therapeutic index

A fit free patient, with no signs of toxicity, requires no levels

How it is done

Steady state takes 2–4 weeks after starting the drug or changing the dose. In the acute ICU setting take daily levels

For IV regimen: loading dose 2–4 hours to assess peak, otherwise predose sampling

For PO regimen: trough level predose

In an emergency, take levels at any time

Interpretation

Phenytoin is largely albumin bound, so in apparent hypoalbuminaemia, an apparently therapeutic level may actually be toxic. Hypoalbuminaemia will lead to an increased fraction of unbound drug. The free fraction is responsible for the pharmacological action of the drug. Total (free plus bound) levels are open to misinterpretation because an apparently ‘normal’ level in a hypoalbuminaemic patient may hide a toxic level of free phenytoin. A conceptual corrected level can be determined, which reflects what the total phenytoin level would be if the patient had normal protein levels. To adjust for a low albumin:

Adjusted phenytoin level = reported level ÷ [(0.02 × serum albumin) + 0.1]

However, this equation depends on the accurate measurement of serum albumin. Some albumin assays are not reliable below 15 g/L

Action Patient showing toxic signs and raised level or level within range:

• Seek expert advice on dose reduction

Patient fitting and levels low:

• Seek advice on repeating a loading dose; and

• Increase maintenance dose as follows:

– <28 μmol/L level, increase daily dose by 100 mg daily

– 28–48 μmol/L level, increase daily dose by 50 mg daily

– 48–64 μmol/L level, increase daily dose by 25 mg daily

Patient fitting and levels are in the therapeutic range:

• Seek expert advice: patient might well need additional/alternative therapy

Before you make a dose change, seek expert advice! NG administration and IV to oral/ng conversion Theoretically one should take account of the different salts of the IV and oral preparation but in practice you can use a 1 to 1 conversion, but give the oral/ng as a single daily dose. Note that enteral feed reduces the absorption of phenytoin liquid so stop feed for 1 hour before and 2 hours after phenytoin administration

Box 10.2 Drugs that affect phenytoin levels in the body

Can increase levels	Can reduce levels
Amiodarone Chloramphenicol Cimetidine Clarithromycin Fluconazole Fluoxetine Fluvoxamine Isoniazid Metronidazole Trimethoprim Voriconazole

Theophylline/aminophylline

See Table 10.4 for the dosing regimen. Serum levels predict the type of adverse effects well, but are less good at predicting severity. Adverse effects of these drugs are outlined in Table 10.5.

Table 10.4 Dosing regimen for theophylline/aminophylline

Loading dose	Aminophylline 5 mg/kg IV over 20 minutes
Maintenance dose	Aminophylline 500 μg/kg/hour IV titrated to plasma levels Oral therapy depends on the brand In the obese patient, use IBW to calculate the dose, as aminophylline distributes poorly in adipose tissue

Indication

Ensure achieving therapeutic target

Avoid toxicity

For IV/PO therapy: TDM is essential, as the drug has a narrow therapeutic range

How it is done

IV infusion: take levels at 1 and 6 hours, repeating daily

Oral therapy: take trough levels after 2–3 days of treatment

Interpretation

Recommended therapeutic range

55–110 μmol/L or 10–20 mg/L

Action In most patients, theophylline has linear kinetics, so doubling the dose will double the serum concentration, but this is not always the case

Acute patient, with low/high level:

• Adjust dose by desired fraction

Acute patient in range:

• Repeat levels daily

Chronic patient, with low/high level:

• Having excluded a reversible cause, adjust the dose

Chronic patient in range:

• Suspected toxicity: consider a second drug or pathology causing toxic signs. You might need to stop theophylline regardless

Symptomatic patient:

• Consider alternative therapy

Important

Beware those in whom the theophylline half-life is increased, i.e. where a normal dose may cause toxicity: cardiac failure, liver failure, the elderly, those taking enzyme inhibitors (e.g. cimetidine, ciprofloxacin)

Beware of those in whom the theophylline half-life is decreased, i.e. where a normal dose may be ineffective: smokers, chronic alcoholics, those taking enzyme inducers (e.g. rifampicin, phenytoin). The effect of smoking can be maintained up to 6 months after cessation

Concurrent systemic salbutamol use may reduce theophylline levels

IV to oral/ng conversion

Converting aminophylline IV to aminophylline oral/ng:

• Calculate 24 hours IV aminophylline requirement to attain desired level

• Use a 1 to 1 conversion to convert IV to oral/ng aminophylline. For ng administration, divide the total dose into 6-hourly doses (although unlicensed, you can give the IV product down the ng tube). For oral dosing use aminophylline modified release products; divide the total dose into 12-hourly dose (round dose up or down, as the tablets are 225 mg)

Converting aminophylline IV to oral/ng theophylline:

• Calculate 24 hours IV aminophylline requirement to attain desired level

• Multiply this by 0.79 for equivalent theophylline dose. Round up or down and convert to the nearest oral product available. Remember modified release products will block the ng tube so are not suitable

Table 10.5 Levels associated with adverse effects of aminophylline and theophylline

Level (mg/L)	Adverse reaction	Frequency (%)
<5	Usually absent	N/A
5–20	Nausea and vomiting	5–10
20–35	As above + diarrhoea, irritability, arrhythmias	25
>35	As above + seizures	80

Vancomycin

There are two methods of vancomycin therapy in use, ‘conventional’ and ‘continuous’ (Table 10.6). When samples are sent off for measurement, it is essential that they are marked with the method of use, as the interpretation of these levels is linked to this method.

Table 10.6 Dosing regimens for vancomycin