Abstract
Invasive mycoses are the substantial cause of morbidity and mortality in immunocompromised children. The prevalence of invasive mycoses in this population is around 25% and the mortality rates are run up to 55-60%. Invasive candidiasis is a major clinical form of systemic fungal infections, and in approximately 60% of all cases in children C. albicans and C. parapsilosis are main causative agents. Efficacy and safety of the therapy are the key characteristics in selection of antimycotics for the therapy of invasive candidiasis in children, but which for a long time was limited to conventional amphotericin B. The entrance of lipid forms of amphotericin B and azoles, especially fluconazole, was the beginning of the new stage in the therapy of candidiasis. The discovery of the echinocandins class and the entrance to the market his first representative – caspofungin – was the principal event in the medical mycology. For nowadays caspofungin is the first antimycotic from echinocandins group which got in July 2008 the official FDA approval regarding his application in children after 3 months of life. In this article a short review about current possibilities in pharmacotherapy of invasive candidiasis in children has been made.
-
1.
Groll A.H., Lehrnbecher T. New antifungal drugs and the pediatric cancer patient: current status of clinical development. Klin Paediatr 2005; 217:158-68.
-
2.
Natarajan G., Lulic-Botica M., Rongkavilit C., et al. Experience with caspofungin in the treatment of persistent fungemia in neonates. J Perinatol 2005; 25:770-7.
-
3.
Steinbach W.J. Pediatric aspergillosis: disease and treatment differences in children. Pediatr Infect Dis J 2005; 24:358-64.
-
4.
Roilides E., Farmaki E., Evdoridou J., et al. Neonatal candidiasis: analysis of epidemiology, drug susceptibility, and molecular typing of causative isolates. Eur J Clin Microbiol Infect Dis 2004; 23:745-50.
-
5.
Boucher H.W., Groll A.H., Chiou C.C., Walsh T.J. Newer systemic antifungal agents: pharmacokinetics, safety and efficacy. Drugs 2004; 64:1997-2020.
-
6.
Odio C.M., Araya R., Pinto L.E., et al. Caspofungin therapy of neonates with invasive candidiasis. Pediatr Infect Dis J 2004; 23:1093-7.
-
7.
Groll A.H., Piscitelly T.J., Walsh T.J. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998; 44:343-500.
-
8.
Chiu N.C., Chung Y.F., Huang F.Y. Pediatric nosocomial fungal infections. Southeast Asian J Trop Med Public Health 1997; 28:191-5.
-
9.
Stamos J.K., Rowley A.H. Candidemia in a pediatric population. Clin Infect Dis 1995; 20:571-5.
-
10.
Abelson J.A., Moore T., Bruckner D., et al. Frequency of fungemia in hospitalized pediatric inpatients over 11 years at a tertiary care institution. Pediatrics 2005; 116:61-7.
-
11.
Zaoutis T.E., Argon J., Chu J., et al. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 2005; 41:1232-9.
-
12.
Raymond J., Aujard Y. Nosocomial infections in pediatric patients: a European, multicenter prospective study. European Study Group. Infect Control Hosp Epidemiol 2000; 21:260-3.
-
13.
Larsen R.A., Powderly W., Kauffman C.A., et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis 2003; 37:634-43.
-
14.
Singhi S.C., Reddy T.C., Chakrabarti A. Candidemia in a pediatric intensive care unit. Pediatr Crit Care Med 2004; 5:369-74.
-
15.
Mokaddas E.M., Ramadan S.A., Aboel Maaty S.H., Sanyal S.C. Candidemia in pediatric surgery patients. J Chemother 2000; 12:332-8.
-
16.
Rodriguez-Nunez A. Incidence and mortality of proven invasive Candida infections in pediatric intensive care patients. Infect Control Hosp Epidemiol 2001; 22:477-8.
-
17.
Almirante B., Rodriguez D., Park B.J., et al. Epidemiology and predictors of mortality in cases of Candida bloodstream infection: results from population-based surveillance, Barcelona, Spain, from 2002 to 2003. J Clin Microbiol 2005; 43:1829-35.
-
18.
Lehrnbecher T., Varwig D., Kaiser J., et al. Infectious complications in pediatric acute myeloid leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93. Leukemia 2004; 18:72-7.
-
19.
Hughes W.T., Armstrong D., Bodey G.P., et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34:730-51.
-
20.
Singhi S., Rao D.S., Chakrabarti A. Candida colonization and candidemia in a pediatric intensive care unit. Pediatr Crit Care Med 2008; 9:91-5.
-
21.
MacDonald L., Baker C., Chenoweth C. Risk factors for candidemia in a children’s hospital. Clin Infect Dis 1998; 26:642-5.
-
22.
Gladdy R.A., Richardson S.E., Davies H.D., Superina R.A. Candida infection in pediatric liver transplant recipients. Liver Transpl Surg 1999; 5:16-24.
-
23.
Soub H., Estinoso W. Hospital-acquired candidaemia: experience from a developing country. J Hosp Infect 1997; 35:141-7.
-
24.
Montane B.S., Mazza I., Abitbol C., et al. Fungal peritonitis in pediatric patients. Adv Perit Dial 1998; 14:251-4.
-
25.
Pappas P.G., Rex J.H., Lee J., et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis 2003; 37:634-43.
-
26.
Ridola V., Chachaty E., Raimondo G., et al. Candida infections in children treated with conventional chemotherapy for solid tumors (transplant recipients excluded): the Institut Gustave Roussy Pediatrics Department experience. Pediatr Blood Cancer 2004; 42:332-7.
-
27.
Krcmery V., Laho L., Huttova M., et al. Aetiology, antifungal susceptibility, risk factors and outcome in 201 fungaemic children: data from a 12-year prospective national study from Slovakia. J Med Microbiol 2002; 51:110-6.
-
28.
Celebi S., Hacimustafaoglu M., Ozdemir O., Ozkaya G. Nosocomial candidaemia in children: results of a 9-year study. Mycoses 2008; 51:248-57.
-
29.
Wisplinghoff H., Seifert H., Tallent S.M., et al. Nosocomial bloodstream infections in pediatric patients in United States hospitals: epidemiology, clinical features and susceptibilities. Pediatr Infect Dis J 2003; 22:686-91.
-
30.
Pfaller M.A., Diekema D.J., Jones R.N., et al. Trends in antifungal susceptibility of Candida spp. isolated from pediatric and adult patients with bloodstream infections: SENTRY Antimicrobial Surveillance Program, 1997 to 2000. J Clin Microbiol 2002; 40:852-6.
-
31.
Krcmery V., Barnes A.J. Nonalbicans Candida spp. causing fungaemia: pathogenicity and antifungal resistance. J Hosp Infect 2002; 50:243-60.
-
32.
Waggoner-Fountain L.A., Walker M.W., Hollis R.J., et al. Vertical and horizontal transmission of unique Candida species to premature newborns. Clin Infect Dis 1996; 22:803-8.
-
33.
Mullen C.A., Abd El-Baki H., Samir H., et al. Nonalbicans Candida is the most common cause of candidemia in pediatric cancer patients. Support Care Cancer 2003; 11:321-5.
-
34.
Trofa D., Gácser A., Nosanchuk J.D. Candida parapsilosis, an emerging fungal pathogen. Clin Microbiol Rev 2008; 21:606-25.
-
35.
Eggimann P., Pittet D. [Candidiasis among non-neutropenic patients: from colonization to infection]. Ann Fr Anesth Reanim 2001; 20:382-8.
-
36.
Pappas P.G., Rex J.H., Sobel J.D., et al. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38:161-89.
-
37.
Sobel J.D., Kauffman C.A., McKinsey D., et al. Candiduria: a randomized, double-blind study of treatment with fluconazole and placebo. The National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis 2000; 30:19-24.
-
38.
Chakrabarti A., Reddy T.C., Singhi S. Does candiduria predict candidaemia? Indian JMed Res 1997; 106:513-6.
-
39.
Azoulay E., Cohen Y., Zahar J.R., et al. Practices in nonneutropenic ICU patients with Candida-positive airway specimens. Intensive Care Med 2004; 30:1384-9.
-
40.
Mermel L.A., Farr B.M., Sherertz R.J., et al. Guidelines for the management of intravascular catheterrelated infections. J Intraven Nurs 2001; 24:180-205.
-
41.
Nucci M., Anaissie E. Should vascular catheters be removed from all patients with candidemia? An evidencebased review. Clin Infect Dis 2002; 34:591-9.
-
42.
Almirante B., Rodríguez D. Antifungal agents in neonates: issues and recommendations. Paediatr Drugs 2007; 9:311-21.
-
43.
Tollemar J., Klingspor L., Ringden O. Liposomal amphotericin B (Am-Bisome) for fungal infections in immunocompromised adults and children. Clin Microbiol Infect 2001; 7(Suppl 2):68-79.
-
44.
Sandler E.S., Mustafa M.M., Tkaczewski I., et al. Use of amphotericin B colloidal dispersion in children. J Pediatr Hematol Oncol 2000; 22:242-6.
-
45.
Knoppert D.C., Salama H.E., Lee D.S. Eradication of severe neonatal systemic candidiasis with amphotericin B lipid complex. Ann Pharmacother 2001; 35:1032-6.
-
46.
Chen T.C., Chen Y.H., Tsai J.J., et al. Epidemiologic analysis and antifungal susceptibility of Candida blood isolates in southern Taiwan. J Microbiol Immunol Infect 2005; 38:200-10.
-
47.
Zaoutis T.E., Foraker E., McGowan K.L., et al. Antifungal susceptibility of Candida spp. isolated from pediatric patients: a survey of 4 children’s hospitals. Diagn Microbiol Infect Dis 2005; 52:295-8.
-
48.
Schwarze R., Penk A., Pittrow L. Treatment of candidal infections with fluconazole in neonates and infants. Eur J Med Res 2000; 5:203-8.
-
49.
Mondal R.K., Singhi S.C., Chakrabarti A., et al. Randomized comparison between fluconazole and itraconazole for the treatment of candidemia in a pediatric intensive care unit: a preliminary study. Pediatr Crit Care Med 2004; 5:561-5.
-
50.
Girmenia C., Venditti M., Martino P. Fluconazole in combination with flucytosine in the treatment of fluconazole-resistant Candida infections. Diagn Microbiol Infect Dis 2003; 46:227-31.
-
51.
de Repentigny L., Ratelle J., Leclerc J.M., et al. Repeateddose pharmacokinetics of an oral solution of itraconazole in infants and children. Antimicrob Agents Chemother 1998; 42:404-8.
-
52.
Antachopoulos C., Walsh T.J. New agents for invasive mycoses in children. Curr Opin Pediatr 2005; 17:78-87.
-
53.
Jeu L., Piacenti F.J., Lyakhovetskiy A.G., Fung H.B. Voriconazole. Clin Ther 2003; 25:1321-81.
-
54.
Walsh T.J., Karlsson M.O., Driscoll T., et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother 2004; 48:2166-72.
-
55.
Keating G.M. Posaconazole. Drugs 2005; 65:1553-67.
-
56.
Gubbins P.O., Krishna G., Sansone-Parsons A., et al. Pharmacokinetics and safety of oral posaconazole in neutropenic stem cell transplant recipients. Antimicrob Agents Chemother 2006; 50:1993-9.
-
57.
Krishna G., Sansone-Parsons A., Martinho M., et al. Posaconazole plasma concentrations in juvenile patients with invasive fungal infection. Antimicrob Agents Chemother 2007; 51:812-8.
-
58.
Pfaller M.A., Messer S.A., Boyken L., et al. Crossresistance between fluconazole and ravuconazole and the use of fluconazole as a surrogate marker to predict susceptibility and resistance to ravuconazole among 12,796 clinical isolates of Candida spp. J Clin Microbiol 2004; 42:3137-41.
-
59.
Muller F.M., Weig M., Peter J., Walsh T.J. Azole crossresistance to ketoconazole, fluconazole, itraconazole and voriconazole in clinical Candida albicans isolates from HIV-infected children with oropharyngeal candidosis. J Antimicrob Chemother 2000; 46:338-40.
-
60.
Rybowicz J., Gurk-Turner C. Caspofungin: the first agent available in the echinocandin class of antifungals. BUMC Proceedings 2002; 15:97-9.
-
61.
Ostrosky-Zeichner L., Rex J.H., Pappas P.G., et al. Antifungal susceptibility survey of 2:000 bloodstream Candida isolates in the United States. Antimicrob Agents Chemother 2003; 47:3149-54.
-
62.
Pfaller M.A., Diekema D.J., Gibbs D.L., et al. Geographic and temporal trends in isolation and antifungal susceptibility of Candida parapsilosis: a global assessment from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. J Clin Microbiol 2008; 46:842-9.
-
63.
Hope W.W., Shoham S., Walsh T.J. The pharmacology and clinical use of caspofungin. Expert Opin Drug Metab Toxicol 2007; 3:263-74.
-
64.
Walsh T.J., Adamson P.C., Seibel N.L., et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005; 49:4536-45.
-
65.
Maertens J., Madero L., Reilly A., et al. A randomized, doubleblind, multicenter trial of caspofungin (CAS) versus (vs) liposomal amphotericin B (LAMB) for empirical antifungal therapy (EAFRx) of pediatric patients (pts) with persistent fever & neutropenia (PFN). 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL: American Society for Microbiology, Washington, DC, USA, 2007 (abstract M-621).
-
66.
Groll A.H., Attarbaschi A., Schuster F.R., et al. Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey. J Antimicrob Chemother 2006; 57:527-35.
-
67.
Jafri H., Zaoutis T.E., Keller N., et al. Prospective, multicenter study of caspofungin (CAS) for the treatment (Rx) of documented fungal infection in pediatric patients (Ped Pts). 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA: American Society for Microbiology, Washington, DC, USA, 2006 (abstract G-873a).
-
68.
Zaoutis T.E., Jafri H., Huang L., et al. Prospective, multicenter study of caspofungin for treatment of documented fungal infections in pediatric patients. 45th Annual Meeting of the Infectious Disease Society of America; 2007 Oct 4-7, San Diego (CA), 78.
-
69.
Available from: www.cancidas.com
-
70.
Hebert M.F., Smith H.E., Marbury T.C., et al. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol 2005; 45:1145- 52.
-
71.
Stone J.A., Xu X., Winchell G.A., et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob Agents Chemother 2004; 48:815-23.
-
72.
Kuse E.R., Chetchotisakd P., da Cunha C.A., et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidiasis: a phase III randomised double-blind trial. Lancet 2007; 369:1519-27.
-
73.
van Burik J.A., Ratanatharathorn V., Stepan D.E., et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39:1407-16.
-
74.
Seibel N.L., Schwartz C., Arrieta A., et al. Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother 2005; 49:3317-24.
-
75.
Queiroz-Telles F., Berezin E., Leverger G., et al. Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy of a randomized double-blind trial. Pediatr Infect Dis J 2008; 27:820-6.
-
76.
European Medicine Agency. Assessment report for mycamine [online]. Available from URL: http://www.emea. europa.eu/humandocs/PDFs/EPAR/mycamine/H734-en6.pdf [Accessed 2008 July 30].
-
77.
Dowell J.A., Stogniew M., Krause D., et al. Assessment of the safety and pharmacokinetics of anidulafungin when administered with cyclosporine. J Clin Pharmacol 2005; 45:227-33.
-
78.
Reboli A.C., Rotstein C., Pappas P.G., et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007; 356:2472-82.
-
79.
Benjamin Jr. D.K., Driscoll T., Seibel N.L., et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother 2006; 50:632-8.
-
80.
Vermes A., Guchelaar H.J., Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 2000; 46:171-9.
-
81.
Rex J.H., Sobel J.D. Prophylactic antifungal therapy in the intensive care unit. Clin Infect Dis 2001; 32:1191- 200.
-
82.
Vardakas K.Z., Samonis G., Michalopoulos A., et al. Antifungal prophylaxis with azoles in high-risk, surgical intensive care unit patients: a meta-analysis of randomized, placebo-controlled trials. Crit Care Med 2006; 34:1216-24.
-
83.
Shorr A.F., Chung K., Jackson W.L., et al. Fluconazole prophylaxis in critically ill surgical patients: a metaanalysis. Crit Care Med 2005; 33:1928-35.
-
84.
Playford E.G., Webster A.C., Sorrell T.C., Craig J.C. Antifungal agents for preventing fungal infections in nonneutropenic critically ill and surgical patients: systematic review and metaanalysis of randomized clinical trials. J Antimicrob Chemother 2006; 57:628-38.
-
85.
Manzoni P., Arisio R., Mostert M., et al. Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: a single-center, 6-year, retrospective cohort study. Pediatrics 2006; 117:e22-e32.
-
86.
Kersun L.S., Reilly A.F., Ingram M.E., et al. Antifungal susceptibility against yeasts isolated from pediatric oncology patients. Med Mycol 2008; 46:337-43.