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Oral step down


(vi) the best available diagnostic tests for diagnosing IC and candidaemia. Although fungi are considered together, the biology, diagnosis and treatment of candida and filamentous fungi are very different.


Candida infection in non- neutropenic patients In patients with Candida septicaemia in non-neutropenic infection who are commenced on an echinocandin, the Infectious Diseases Society of America (IDSA) recommends step-down therapy to fluconazole in patients when they are clinically stable and if the Candida species is likely to be susceptible to fluconazole. Voriconazole is recommended if additional mould coverage is desirable. The IDSA recommends three to five days of therapy with an echinocandin before switching to oral fluconazole, but recognises that there are no data to support the timing of step-down.9


The European Society for Clinical Microbiology and Infectious Diseases10 recommends Step-down to fluconazole after 10 days of IV, if species is susceptible, patient tolerates PO, and patient is stable


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De-escalation strategies (switch from IV echinocandin therapy after initial response to oral therapy with an azole antifungal drug) are commonly used. However, criteria for ‘early switch’ (for example, after three to five days) are not clearly established in contrast to ‘late switch’ after ten days of effective therapy as recommended in current guidelines. A recent study in non-neutropenic patients showed that a change from IV anidulafungin to oral fluconazole/ voriconazole at five days was safe and effective as long as patients had the ability to tolerate oral therapy, had been afebrile for>24 hours are haemodynamically stable and had documented clearance of Candida from the bloodstream.11 Overall, in non-neutropenic candida infections, there is consensus that after improvement in clinical signs, sterilisation of blood cultures and documented in vitro susceptibility of the causative yeast, step-down therapy after initial treatment with an echinocandin (anidulafungin, caspofungin and micafungin) was shown to be effective with oral fluconazole (or voriconazole) starting on day 10 of antifungal therapy and may be recommended if oral drug intake and gastrointestinal absorption are possible.12–14 Implementation of these


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recommendations may however be troublesome, because in 2009, only 38% of microbiology laboratories in the UK carried out antifungal susceptibility.15


Mould infection in non-neutropenic patients For moulds, there are no studies looking at IV to oral switch. However, there are a number of kinetic studies showing that oral voriconazole achieves therapeutic levels in patients studied, but these studies did not include haem-onc patients.16,17


Fungal infections in haem-onc patients


There are a number of potential problems that occur during the management of haem-onc patients and which may make the use of oral switch therapy problematic. For most oral antifungals, the pharmacokinetic profiles of the oral drug is well characterised. However, in common with all oral drugs, the most common practical consideration for clinical use is variable gastrointestinal absorption, which includes factors such as high dietary fat content and gastric pH. Additional problems in cancer patients include chemotherapy-associated mucositis and in stem cell recipients, gut-associated graft-versus-host disease, which may cause more variability in the blood levels of the antifungal drug. For posaconazole, even with its limited metabolism by cytochrome P450 (CYP450), it is crucial to review the patient's medication record before initiating therapy and in many instances a change in choice of drug, dose alteration or close serum level


monitoring may be needed.18


Knowledge of the pharmacokinetics and pharmacodynamics of antifungal agents for infants and children remains incomplete, so the position is even more complex in this patient group.19


Different


antifungal agents differ: for voriconazole, it is known that in immunocompromised children that younger age and the presence of CYP2C19 gain-of-function alleles are associated with subtherapeutic voriconazole concentrations.20


However,


another study concluded that voriconazole had acceptable safety and useful efficacy in the management of paediatric invasive fungal diseases. Pharmacokinetic variability was high and no predictable dose–concentration effect relationships were observed.21


This study


underlines the need for therapeutic drug monitoring when pharmacokinetics are unpredictable.


Another potential problem with oral stepdown therapy in haem-onc patients is that a diagnosis of invasive fungal infection is made either on grounds of clinical or radiological suspicion and without a fungal isolate being available. Antifungals differ in spectrum of activity, and these differences are critical when selecting the antifungal most likely to provide success for a patient with an invasive fungal infection. When the species has not yet been identified, an analysis of regional epidemiology and risk factors can provide clues as to the most likely pathogen.22


In this case, the clinician will often prefer to continue with an agent with a broader spectrum.


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