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• W1832541874 abstract "Invasive fungal infections (IFI) continue to constitute a majorchallenge to treating physicians as a result of the increasednumber of cases and the high mortality. Close collaborationamong physicians, mycologists and pharmacologists is neces-sary in order to exploit new treatment and diagnostic modal-ities and to optimize the use of those already available, withthe ultimate goal of improving the outcome of IFI. In thisissue of the journal, we present reviews from representativesof each of these specialties.Hope and Drusano [1] review the approach of predictingthe optimal dosing of systemic antifungals based upon experi-mental models and pharmacokinetic/pharmacodynamic analy-sis. It is difficult to design and conduct clinical trials that, in acomprehensive way, provide exhaustive data on dosing regi-mens and outcome relationships in a disease entity whereoutcome is influenced by a number of factors in addition tothe infection itself. Consequently, clinical experience overtime may reveal that initial dosing regimes are suboptimal.Graninger et al. [2], as early as 1993, demonstrated the cor-relation between fluconazole dosing and clearance of theblood stream during candidaemia, comparing 5 and 10 mg/kgper day. The response rate was 60% vs. 83%, the failure toclear candidaemia 2/30 vs. 0/30 and the attributable mortality8/30 vs. 1/30 (p 0.0258). Clancy et al. [3], in 2005, demon-strated the correlation between dose/MIC and treatmentoutcome for candidaemia and fluconazole, with an increasingnumber of failures occurring when the dose/MIC ratio fellbelow 50 (p 0.0003). Subsequently, Pai et al. [4] also incorpo-rated the weight and showed a more than three-fold differ-ence in mortality upon comparing patients with a dose/kg/MIC between 0–5 and >10, respectively (p 0.03). Finally, Ga-rey et al. [5] demonstrated that, in a cohort of 206 candidae-mic patients from four medical centres in the USA, 55% ofthe patients received inadequate empirical dosing (<400 mgor <6 mg/kg) and 47% of the patients did so after speciesidentification based on the guidelines of the Infectious Dis-eases Society of America (400 mg or 6 mg/kg per day forinfections caused by species other than Candida glabrata andCandida krusei and 800 mg or 12 mg/kg for C. glabrata infec-tions). As a result of such studies, the recommended dailydose has been increased and awareness has emerged thatoverweight patients and patients with C. glabrata infectionsare at risk of being underdosed, despite the current recom-mendations. As illustrated in this theme section, experimen-tal models and pharmacokinetic/pharmacodynamic analysiscan contribute to a better prediction of optimal dosing regi-mens with respect to size and frequency of doses [1].The highest incidence of candidaemia per age group isobserved in the neonatal population, with incidence rates of10–40/100 000 population [6–9] and children with underlyinghaematological disease are at risk of invasive mould infec-tions [10]. Yet, the diagnosis and management of invasivefungal infections in the paediatric setting is less well studiedthan in adults. A number of new antifungal compounds havebeen launched over the recent decades and their role in themanagement of adult infections has been established. How-ever, not all of these compounds have been thoroughly stud-ied in children and, because of the different pharmacokineticprofiles, the adult dosing regimens cannot be directly trans-lated. The diagnostic armamentarium has evolved consider-ably over the recent decades, with improved culture media,rapid species identification tests and surrogate markers forinvasive Candida and Aspergillus infections having been devel-oped and marketed. The diagnostic sensitivity of antigen andPCR testing depends largely on the number of samples takenand, in both cases, testing at least twice weekly during riskperiods is recommended and associated with higher sensitiv-ity [11,12]. Furthermore, the benefit of such screening regi-mens in terms of more targeted antifungal treatment andreduced cost has been demonstrated in several studies [13–15]. Yet still a number of infections go undiagnosed [16] orare diagnosed at a late stage, with a consequently pooreroutcome [17,18]. Part of this is probably the result of fungibeing slower growing and present intermittently, or in loweramounts, in the clinical samples compared to bacteria.However, part of the reason may also be that these newmarkers are not used optimally, if at all, or, although labora-tories perform well in traditional external quality assessmentschemes, and thus do not lack professional skills, the level of" @default.
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• W1832541874 date "2009-07-01" @default.
• W1832541874 modified "2023-09-28" @default.
• W1832541874 title "Invasive fungal infections: past achievements and challenges ahead" @default.
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• W1832541874 doi "https://doi.org/10.1111/j.1469-0691.2009.02914.x" @default.
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