Canterbury DHB

Invasive Aspergillus Infection (IAI) / Fungal PCR Tests

Aspergillus is generally acquired through the inhalation of aerosolised spores.

Fungal PCR Tests

These tests are not reliable enough to provide an absolute guide to the management of patients with suspected fungal infection. However, PCR results can be used as one of the factors to consider when the diagnosis of IAI is a possibility. A negative PCR may help to decide when to stop antifungal therapy. It is recommended that blood be taken (-5 mL EDTA) for “Aspergillus PCR analysis” in accordance with the recommendations given in the Fungal Prophylaxis section.

Voriconazole

Voriconazole is our usual first line treatment for suspected invasive aspergillus infection, scedosporium, fusarium sp, and other serious fungal infections. It is not reliably active against mucor species or other zygomycetes. Voriconazole can be used in both oral and intravenous formulation.

It is absorbed very well and therefore the intravenous preparation is generally used when patients are nil by mouth or they have significant malabsorption.

Dosage and Administration

Oral

• Patients > 40 kg: loading dose – 400 mg Q12H for 24 hours (2 doses) maintenance – 200 mg BD.
• Patients < 40 kg: loading dose – 200 mg Q12H for 24 hours (2 doses) maintenance – 100 mg BD.

Voriconazole has good oral availability (approx 96%). Administer on an empty stomach – one hour before or two hours after food.

In patients with an inadequate therapeutic response, the oral dose of voriconazole may be increased to 300 mg BD (> 40 kg) and 150 mg BD (< 40 kg). See Therapeutic drug monitoring (below) before increasing the dose.

IV

• Loading dose – 6 mg/kg IV Q12H for 24 hours (2 doses).
• Maintenance – 4 mg/kg Q12H.

Where possible, round to the nearest vial size of 200 mg.

The IV dose must be infused over 1-2 hours (maximum rate is 3 mg/kg/hour) at a maximum concentration of 5 mg/mL (it is not given as a bolus injection). If patients are intolerant the dose can be decreased to 3 mg/kg every 12 hours.

Reactions have occurred with IV voriconazole. Symptoms include:

• Very common (≥ 10%): fever; headache; GI upset; visual disturbances including photophobia (usually lasts <24 hours); rash; peripheral oedema.

  Note: Visual disturbances can be frightening.

• Common (≥ 1% to < 10%): acute renal failure; haematuria; injection site reaction; oedema; flu-like syndrome; hypotension; thrombophlebitis; elevated LFTs, creatinine; hepatic toxicity; blood dyscrasias; hypokalaemia; hypoglycaemia; CNS effects including hallucination; respiratory distress syndrome; photosensitivity.

Therapeutic drug monitoring

Blood levels can be taken for voriconazole to ensure adequate plasma levels are achieved. This is usually indicated only if there is a concern with compliance, suspected impairment of drug absorption, or if there is an inadequate clinical response prior to a proposed dose increase.

• A trough level is taken from a single ‘red top’ tube.
• Aim for a trough level between 1-5 mg/L. As at 1 December 2016, Eclair reference range still shows as 0.5-2.5 mg/L, but this is being updated to 1-5 mg/L as recommended by ID.
• Following a loading dose, steady state concentrations should be reached within 24 hours or 6 days after twice daily dosing.

Dosage adjustments

In patients with mild to moderate hepatic cirrhosis, the maintenance dose should be decreased by 50%. (The loading dose should remain the same.)

In patients with moderate to severe renal impairment (< 0.6 mL/sec or < 50 mL/min), it is best to avoid IV formulation due to the possible accumulation of [preservative] compound present in the IV preparation. Oral dosing does not need to be altered.

Other information

When initiating oral voriconazole following treatment with IV amphotericin, ensure one overlapping dose of IV amphotericin is given during the 24 hour loading dose of voriconazole.

For more information about voriconazole, see the Voriconazole Data Sheets on Medsafe.

For more information about Therapeutic Drug Monitoring, see the Pink Book.

Liposomal Amphotericin B

Consider liposomal amphotericin therapy in consultation with the ID team where a patient has proven or probable invasive pulmonary aspergillosis that is not responding to azole therapy.

Administration and Dosage

Pre-hydration is not required. Infuse AmBisome® in 50-100 mL glucose (dextrose) 5%, over 30 - 60 minutes. Commence at a dose of 1 mg/kg/day, which can be increased up to 3 mg/kg/day if initial response is inadequate. The peak serum concentration after 3 mg/kg dose is 10-35 mg/l.

Note:

• AmBisome® is incompatible with sodium chloride 0.9%.
• Vial size is 50 mg, so round to the nearest 50 mg when charting.

Some studies have suggested lesser efficacy of lipid formulations compared to amphotericin B when administered in equivalent doses. Furthermore, lipid binding may prevent AmBisome® penetrating the tissues early in the course of therapy. Therefore, a build-up phase with lower doses of AmBisome® may reduce initial efficacy.

Side Effects

• Hypokalaemia, hyponatraemia – give supplements as required.
• Mild rise in creatinine, abnormal LFTs – consider reducing dose or commence other agent.
• Rigors – give pethidine 50 mg IV (may be required as a premedication).
• Anaphylactic reactions – presenting as hypotension, erythema, bronchospasm, and facial oedema. Stop infusion and give adrenaline (1 mL of 1:1000) IV and hydrocortisone 200 mg IV immediately.

For more information, see the Liposomal Amphotericin Data Sheets on Medsafe.

Caspofungin

Consider using caspofungin as salvage therapy for patients who are refractory or intolerant to other anti-fungal treatment. This product is registered for use with patients who have proven invasive aspergillus. It is active against most candida species as well as aspergillus. It is not active against cryptococcosis, fusarium, mucor, and some other fungal species. The treatment dose is 70 mg, given as a loading dose IV on day 1 of treatment. 50 mg IV is given daily for continuing treatment.

It doesn't cause hypokalaemia or renal impairment.

For more information about caspofungin, see the Caspofungin Data Sheets on Medsafe.

Posaconazole

Consider posaconazole in consultation with ID team for treatment for non-aspergillus filamentous fungi (e.g. mucor species) unless susceptible to voriconazole on in-vitro testing.

Topic Code: 9477