Invasive fungal infections and antifungal therapy

Invasive fungal infections are an important cause of morbidity and mortality after allogeneic SCT with a frequency of 10-25% and mortality of >70%.

Pathogenesis

• Majority of infections are due to Candida species and Aspergillus species though infections due to other opportunistic fungi increasing (Trichosporon spp., Fusarium spp., Bipolaris spp. and Zygomycetes amongst others.

• Invasive Candida infections classified as candidaemia or acute disseminated candidiasis and arise from invasion of bloodstream from infected mucosal surfaces or via central venous catheters; decreasing incidence due to introduction of fluconazole prophylaxis though increased non-albicans spp. (esp. glabrata and krusei).

• Invasive Aspergillus infections affect paranasal sinuses and lungs and arise from airborne exposure; increasing incidence, particularly late

330 after transplantation.

• Risk factors: prolonged and profound neutropenia; use of corticos-teroids.

Prophylaxis

• Prophylaxis: high efficiency (>90%) particulate air (HEPA) filtration or positive pressure ventilation; prophylaxis with fluconazole (400mg/day does not cover Aspergillus spp., C glabrata or C krusei) or itraconazole (200-400mg/day; poor absorption from capsules; extremely unpalatable liquid preparation).

Amphotericin

• If a febrile neutropenic transplant patient is unresponsive to second line antibiotics after 48-96h and/or there is a suspicion of possible fungal infection (unwell; chest symptoms; peripheral nodules, halo sign or cavitation on CT chest, evidence of candidaemia), then standard formulation of amphotericin (Fungisone™) should be started.

• Give test dose of 1mg IV over 30 mins with observation of the patient for abreaction for 30 mins followed by 1mg/kg daily.

• Daily urea and electrolytes are recommended and amiloride 5mg (increasing to 10mg if required) should be prescribed to counteract the frequently accompanying hypokalaemia. Oral K+ supplements often required. Serum Mg2+ and LFTs should be checked twice weekly.

• All doses of amphotericin should be preceded by a 0.9% saline preload. 500mL 0.9% saline should be infused as fast as tolerated (usually over 1h)—reduces nephrotoxicity and side effects. Paracetamol 1g PO should be given 30 minutes prior to infusion together with chlorpheniramine 10mg IV. Pethidine 25-30mg IV stat may be given if a troublesome reaction occurs.

Liposomal amphotericin

Suggested indications for prescribing a liposomal or other lipid formulation of amphotericin.

1. Refractory fever >72h on standard amphotericin at 1mg/kg.

2. A rise in the creatinine to >50% baseline levels with standard amphotericin despite optimal hydration.

3. Deteriorating LFTs.

4. Evidence of severe disseminated fungal infection-ie multiple lesions on CXR or CT scan, or any two sites of sinuses, lung, liver, spleen or brain.

5. Patients receiving cyclosporin after an allograft. These patients should receive lipid formulation product if baseline creatinine is >130|jmol/L. Otherwise, the indication for lipid formulation product is as in 1-4 above.

Lipid formulation amphotericin products

2 lipid formulations of amphotericin in extensive use—both expensive. No comparative trial of the 2 products but efficacy data appear similar. An appropriate protocol is suggested:

Commence either liposomal amphotericin (AmBisome™) at 1-5mg/kg/day or amphotericin B lipid complex (Abelcet™) at 2.5mg/kg (in practice round up or down to standard vial size to avoid wastage and minimize cost). Follow data sheet instructions carefully, observing for anaphylaxis. The dosage should be increased to a maximum of 5mg/kg Abelcet™ or 3-5mg/kg AmBisome™ in patients who have either a confirmed mycological diagnosis or a fever which does not respond within 72h on the lower dose.

Paracetamol and chlorpheniramine pre-medication cover is advised for Abelcet™ (may also be required for AmBisome™). 0.9% saline preload is not normally required unless renal or liver function deteriorate during treatment. Renal function should be checked on alternate days for the duration of the treatment. Serum Mg2+ and LFTs should be checked weekly.

Total duration of treatment difficult to asses. General principles are that therapy should continue for at least 2 weeks and until neutrophil recovery and no signs of progression radiologically.

Voriconazole

A second-generation triazole that has been shown to be superior to amphotericin in antifungal efficiency and survival in an international randomised trial and likely to become treatment of choice for invasive aspergillosis due to more favourable toxicity profile. Dose 6mg/kg IV bd day 1 then 4mg/kg IV bd maintenance converting to oral 200mg bd (may commence orally with 400mg bd loading dose on day 1). No dose adjustment required for renal or acute hepatic impairment but monitor renal and hepatic function. Side effects: visual disturbances, rash, elevated LFTs and with IV administration, flushing, fever, tachycardia and dyspnoea.

Caspofungin

An echinocandin which targets the fungal cell wall and is active against Candida and Aspergillus spp. Higher response rate demonstrated in comparison to amphotericin in treatment of invasive candidiasis. Loading dose

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