Future Directions Prevention of Fungal

age and, especially, infant HSCT recipients are at highest risk for PCP infection Kim et al. 2008 b .

14.4.2 Approaches to PCP Prophylaxis

PCP reactivation or infection is generally thought preventable in patients with cancer with adminis- tration of classical prophylaxis with trimethoprim- sulfamethoxazole TMP-SMX. However, in the setting of alternative prophylaxis agents or TMP- SMX noncompliance, episodes of PCP do still occur beginning about 2 months following initia- tion of chemotherapy and continuing through recovery of T-cell functional immunity. TMP acts by interfering with dihydrofolate reductase, inhib- iting synthesis of tetrahydrofolic acid and thus nucleic acid synthesis. TMP-SMX administration in conjunction with antifolates for ALL treatment can lead to marrow suppression and may require lowering of chemotherapy doses Levinsen et al. 2012 . The necessary amount of TMP-SMX required to prevent PCP has not been well stud- ied, and a variety of dosing regimens exist, with 2 or 3 days per week administration being the most common Agrawal et al. 2011 . Generally, TMP- SMX is continued for at least 3 months following chemotherapy, though this recommendation is not evidence-based as studies have shown a variable rate of T-cell recovery after chemotherapeutic regimens, potentially dependent on patient age and chemotherapeutic intensity Mackall et al. 1995 ; Azuma et al. 1998 ; Mazur et al. 2006 . In addition to possible bone marrow sup- pression, many patients have allergies or other reactions to TMP-SMX that induce clinicians to prematurely discontinue its use. However, the optimal second-line prophylactic agent is not well defi ned and all options appear to be potentially less effective than TMP-SMX. Agents that have been used include oral dapsone, intravenous or inhaled pentamidine and oral atovaquone. Dapsone is inexpensive but has a high incidence Table 14.5 Graded recommendations for interventions to prevent fungal infections in pediatric oncology patients Grade Comments References Data from studies of adult or adolescent patients a Data from studies of or including pediatric patients a Antifungal prophylaxis should generally not be utilized for patients with newly diagnosed ALL None Antifungal prophylaxis with fl uconazole should be considered for patients undergoing reinduction for relapsed ALL b None Antifungal prophylaxis with a minimum of fl uconazole can be considered for patients undergoing chemotherapy for AML although pediatric evidence is mixed 1A 1B b Antifungal prophylaxis with an echinocandin or posaconazole can also be considered; there is no accepted dose of posaconazole for children 13 years of age Mattiuzzi et al. 2006 ; Cornely et al. 2007 ; Robenshtok et al. 2007 ; Lehrnbecher et al. 2009 ; Sung et al. 2013 ; Science et al. 2014 Antifungal prophylaxis should generally not be utilized for patients with solid tumors 2B Science et al. 2014 ALL acute lymphoblastic leukemia, AML acute myelogenous leukemia a Level of evidence per Guyatt et al. 2006 ; see Preface b Area in urgent need of further investigation 14