Selected management issues of invasive fungal infections

Treatment and prevention of neonatal invasive candidiasis

As outlined earlier, preterm infants of very low birth weight are at considerable risk to develop invasive Candida infections. In the U.S., Candida spp. currently represent 9-13% of blood culture isolates obtained from NICUs. More recent case series indicate infection rates of s 5% in infants of < 1500 g birth weight; infection rates in infants < 1000 g, however, are between 8% and 28%. In contrast, the epidemiology of invasive Candida infections in European countries has been less well investigated; however, infection rates appear to be considerably lower than those in the U.S.

Invasive Candida infections in preterm infants are caused predominantly by C. albicans and C. parapsilosis. They are associated with intravas-cular catheters, intracranial shunt systems, use of broad-spectrum antibacterial agents and corticosteroids, mucocutaneous colonization and parenteral hyperalimentation. While most cases present with candidemia, disseminated infection involving skin, kidneys, lungs and in particular the central nervous system is common.

Current options for treatment of invasive Candida infections in preterm neonates include amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC) [221], liposomal amphotericin B [228, 229], and fluconazole [260-263]. The usefulness of amphotericin B may be curtailed by renal adverse events, and that of fluconazole by the compound's limited spectrum and dosing issues in the first days of life. Based on their excellent safety and tolerance and broad spectrum, mostly cidal activity against Candida spp., the new class of echinocandin lipopeptides may offer alternative options in the future [362, 363]. Independent of the individual choice of treatment, however, removing potentially contaminated intravascular catheters and devices and appropriate supportive care are prerequisites for successful outcome.

A randomized, placebo-controlled, double-blind, single-center clinical trial conducted in the U.S. has demonstrated that fluconazole may prevent invasive Candida infections in very low birth weight premature infants without impact on overall survival [279]. Further studies lend support to the preventative efficacy of fluconazole in high-risk premature infants [282-286]. Therefore, fluconazole prophylaxis is a valid option for centers with a high frequency (> 10%) of invasive Candida infections in premature infants of < 1000 g birth weight or in the setting of a nosocomial outbreak by a fluconazole-susceptible Candida species.

Choice of antifungal agents and duration of therapy

Rational selection of the initial drug of choice is based on the susceptibility of the offending fungus, the type and site of infection, host-based factors such as the severity of immunosuppression and preexisting organ dysfunctions, pharmacokinetic and pharmacodynamic characteristics, and adequate documentation of activity for the particular indication in clinical trials. A guide to the selection of antifungal agents for the treatment of deeply invasive fungal infections agents and pediatric dosage recommendations are provided in the tables. These recommendations are based on the published adult and pediatric literature and the personal expertise of the authors.

The duration of therapy is ill defined for the majority of deeply invasive infections. In uncomplicated candidemia, daily blood cultures should be obtained until defervescense of the patient, and a course of 14 days of therapy after sterilization of the bloodstream is given [28, 106, 257]. Similarly, in uncomplicated HIV-associated cerebral cryptococcosis, DAMB, preferentially in combination with 5-FC, is given for a minimum of 2 weeks as induction therapy, to be followed by consolidation and maintenance with fluconazole [266, 267]. For most other infections, however, no uniform recommendations can be made. Responses to treatment in opportunistic fungal infections are difficult to monitor, and in many circumstances, stabilization can be considered a success. For example, pulmonary lesions in invasive aspergillosis may progress during the first week of therapy without necessarily indicating treatment failure [381]. However, the clinical situation needs to be reassessed continuously and alternative agents be considered when there is clear deterioration despite appropriate antifungal treatment. Prolonged, individualized therapy and a multidisciplinary approach are required and treatment should be administered until complete resolution of all signs and symptoms and abatement of the underlying deficiency in host defenses. It is important to realize that patients with invasive mold infections who respond and do not succumb to their underlying condition may require treatment for months and sometimes, years.

Adjunctive interventional therapies

Adjunctive interventional therapies for invasive yeast infections include the removal or the exchange of potentially infected catheters, the removal of infected artificial implants and, as appropriate, the surgical debridement of focal lesions [106, 257].

For Aspergillus spp. and other opportunistic moulds, surgery is indicated for any infected foreign material, for lesions of the skin or/and adjacent soft tissues, and endocarditis, endophtalmitis, and osteomyelitis. It may be indicated for amenable processes located in the brain and other deep tissue sites. Surgery is also a necessary adjunct in the treatment of invasive sinusitis; however, in the neutropenic host, it should be minimally invasive for aeration and diagnostic purposes only. Indications for surgery in invasive pulmonary aspergillosis include lesions impinging on great vessels or major airways, major hemopthysis from a focal lesion, and lesions progressing into pericardium, thoracic wall, and abdominal cavity [28, 106]. Larger series including neutropenic patients reported minor perioperative morbidity and mortality with pulmonary surgery for mould infections [382-385]. Whether surgery is always indicated for residual lesions in patients who survive a pulmonary mould infection and need to proceed with further myelosuppressive treatment or a bone marrow transplantation, is unclear [384]. However, patients should have had at least a partial response, and should receive continuous and appropriate antifungal chemotherapy.

Adjunctive immunotherapies

Reversal of the underlying impairment of host defenses is paramount to successful treatment of invasive fungal infections. This may include discontinuation or at least dose-reduction of concomitant glucocorticosteroids, if feasible. Cytokines, such as granulocyte (G)-colony-stimulating factor and granulocyte-macrophage (GM)-colony-stimulating factor may decrease the duration of neutropenia and increase the function of phagocytic cells [386]. Administration of colony-stimulating factors, such as G- or GM-colony-stimulating factors, to neutropenic patients with an invasive fungal infection is strongly advocated, although definite conclusions about efficacy can not be inferred [387, 388]. Other cytokines such as IFN-y, interleukin (IL)-12 and IL-15, and neutralizing antibodies to IL-4 and IL-10 have been shown to have useful effects in certain experimental settings and need to be evaluated [389-391]. Lastly, the indication of growth factor-elicited granulocyte transfusions is still unclear and will have to be defined in controlled clinical studies [392, 393].

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