Findings from the current review have helped ascertain the association between various manifestations of mucormycosis, their respective predisposing factors and causative organisms.

A randomized, double-blind, placebo-controlled trial assessed the efficacy and toxicity of 400 mg/day fluconazole in preventing fungal infections during the first 75 days after marrow transplantation. During prophylaxis, systemic fungal infections occurred in 10 (7%) of 152 fluconazole-treated patients compared with 26 (18%) of 148 placebo-treated patients (P = .004). There were no Candida albicans infections in fluconazole recipients compared with 18 in placebo recipients (P < .001) and no significant increase in Candida infections other than C. albicans. Fluconazole also significantly reduced the incidence of superficial fungal infections (P < .001), fungal colonization (P = .037), and empiric amphotericin B use (P = .005). The probability of survival was improved in fluconazole recipients, in whom 31 deaths occurred up to day 110 after transplantation compared with 52 deaths in placebo recipients (P = .004). No clinically significant toxicity was detected with fluconazole use. Prophylactic fluconazole was safe and significantly reduced systemic fungal infections with other benefits, including improved survival at day 110 after marrow transplantation.

This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections. The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤ 2 μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC₉₀) values are typically <2 μg/mL but 100-fold higher MIC₉₀ values are seen with Candida parapsilosis (1-2 μg/mL) and Candida guilliermondii (1-4 μg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed. Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2 μg/mL. Of the three echinocandins, the in vitro 'paradoxical effect' (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin. All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9-20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potenti...

Pfizer.

Neurological C. gattii disease predominates in the Australian endemic setting. Lumbar puncture and cerebral imaging, especially if serum CRAG titers are ≥512, are essential. Long-term follow up is required to detect late neurological complications. Immune system evaluation is important because host immunocompromise is associated with reduced survival.

The efficacy of voriconazole in 107 patients with scedosporiosis was analyzed. Principal infection sites were the lungs/sinuses (24%), central nervous system (CNS) (20%), and bone (18%), while 21% of patients had disseminated infection. Solid organ transplantation (22%), hematological malignancy (21%), and surgery/ trauma (15%) were the predominant underlying conditions. A successful therapeutic response was achieved in 57% of patients (median, 103 therapy days), with >98% of those responding receiving >28 days of therapy. Patients receiving primary therapy showed a 61% response versus 56% for the others. The best therapeutic responses were seen for skin/subcutaneous (91%) or bone (79%) infections, and the lowest for CNS infections (43%). Patients without major immune suppression (72%) or those with solid organ transplantation (63%) or various hematological conditions (60%) showed the best responses by underlying condition. Median known survival time was 133 days (therapy successes, 252 days; failures, 21 days). In all, 43 (40%) patients died, 73% due to scedosporiosis. Patients with Scedosporium prolificans infection had significantly reduced survival times (P ‫؍‬ 0.0259) and were more likely to die from fungal infection (P ‫؍‬ 0.002) than were Scedosporium apiospermum-infected patients. In a subset of 43 patients where voriconazole baseline MICs were available, response to voriconazole was higher for S. apiospermum-infected patients (54% response; MIC 50 , 0.25 g/ml) than for S. prolificans-infected patients (40% response; MIC 50 , 4.0 g/ml). Voriconazole demonstrated clinically useful activity in the treatment of both S. apiospermum and S. prolificans infections and was well tolerated.

The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD).

This study identifies significant differences in candidemia in neonates, children, and adults. Neonatologists and pediatricians must consider age-specific differences when interpreting adult studies and developing treatment and prevention guidelines.