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Anna Cosnahan
Introduction
Invasive fungal infections among immunocompromised children remain a major cause of
mortality, with rates trending as high as 88 percent. These fungal infections may be caused by a variety of
organisms, but the most common sources are Candida and Aspergillus, with molds causing a higher
degree of mortality.1 There is evidence that Aspergillus infections are actually increasing in incidence in
the immunosuppressed population. Cystic fibrosis patients at Johns Hopkins University demonstrated an
20 percent increased incidence in growth of filamentous fungi, Aspergillus fumigatus in particular, in
respiratory tract specimens collected over a span of 10 years.2 Based on this information, early detection
and appropriate treatment, as well as strategic prophylaxis in particularly susceptible high-risk
individuals, is particularly important.
Specific risk factors place patients at increased risk of invasive fungal infections. Some of those
include, but are not limited to, burns, HIV infection, hematopoietic stem cell transplantation, solid organ
transplantation, neutropenia due to chemotherapy, and cystic fibrosis.3 Other risk factors may include
central vascular catheterization, abdominal surgery, steroid use, and prior exposure to broad-spectrum
antibiotics.4 The latter two are particularly pertinent when considering cystic fibrosis patients, who may
be on long term broad spectrum antibiotics for a chronic state of colonization as well as oral and inhaled
steroids.2,4 Despite the severity of invasive fungal infections, it is still considered to be the standard of
care that only the highest risk individuals are on antifungal prophylaxis.4 These patients would be those
with hematopoietic stem cell transplantation, receiving chemotherapy from acute myeloid leukemia or
relapsed acute lymphoblastic leukemia and patients with severe aplastic anemia. Considering these
individual risk factors, as well as culture results and highly likely pathogens, is important when selecting
a therapeutic agent for an indication of prophylaxis or treatment.
There are several antifungal drugs utilized for the prevention and treatment of invasive fungal
infections in the pediatric population, but the one focused on for this retrospective study was azoles
(Table 1). Azoles, specifically the triazoles, are used for both prophylaxis and treatment. For pediatric
patients, fluconazole is considered first line for prophylaxis and can also be used for treatment, though
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issues with resistance may require a more aggressive treatment option like itraconazole or voriconazole. 4
Fluconazole has excellent coverage of Candida with the exception of C. glabrata and C. krusei, as well as
good bioavailability, and does not require an acidic environment for optimal absorption.5 Voriconazole
and itraconazole, the focus of this particular retrospective study, are other agents used for prophylaxis and
treatment of invasive fungal infections. Their advantages include a broader spectrum of activity,
particularly against Aspergillus, though voriconazole does have slightly superior bioavailability.5
However one consideration for these agents is their need for an acidic environment for absorption.
Posaconazole, a newer agent, has even broader coverage, albeit with limited but growing data in
pediatrics currently. The limitation on data in pediatrics does not only pertain to posaconazole, but all of
the azole drugs. Data for the use of these agents is largely extrapolated from adult data, but the concern is
that children do not exhibit the same pharmacokinetics as adults, which may affect the effectiveness of
dosing strategies. Children, for example, may exhibit a hypermetabolic state, particularly cystic fibrosis
patients, requiring higher doses to remain therapeutic.5 Hepatic and renal function are also developing and
significantly distinct from adults which can affect the metabolism and elimination of these drugs, and in
turn, their efficacy.
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Table 1. Azole Agent Characteristics
Activity
Indication
Formulations
Absorption
Metabolism
Side Effects
Monitoring
Fluconazole
Yeasts (exception:
C. glabrata,
C. krusei)
Prophylaxis
Oral, IV
Food does not
affect (>90%
bioavailability)
2C19, 2C9, 3A4
Liver toxicity
Renal and liver
function, serum
electrolytes
Itraconazole
Yeasts, Aspergillus
Voriconazole
Yeasts,
Aspergillus
Prophylaxis,
Treatment
Oral
Requires gastric
acidity
Prophylaxis,
Treatment
IV, Oral
Requires gastric
acidity
3A4
Nausea, vomiting,
abdominal pain,
liver toxicity
2C19, 2C9, 3A4
Liver toxicity,
rash,
photophobia/
hallucinations,
increase in SCr
Renal and liver
function, TDM,
serum
electrolytes
Renal and liver
function, TDM
Posaconazole
Yeasts,
Aspergillus,
Zygomycetes
Prophylaxis,
Treatment
Oral, IV
Requires gastric
acidity & food fat
content
3A4
Liver toxicity,
nausea, vomiting,
abdominal pain,
thrombocytopenia,
neutropenia
Renal and liver
failure
With the extrapolation of data, there is an even greater importance placed on therapeutic drug
monitoring, recommended for itraconazole and voriconazole, as sub-therapeutic concentrations lead to a
higher probability of mortality.6 One of the questions this study attempts to determine is if therapeutic
drug monitoring is actually done; yet another is the relationship between weight-based dosing and serum
concentrations achieved. Another consideration when appropriating a dose for these agents is drug
interactions, particularly with immunosuppressants. As CYP3A4 inhibitors, azoles may result in a slight
increase in cyclosporine and tacrolimus concentrations, an interaction documented consistently across
three different azoles in a study by Doring and colleagues which ultimately required a dose adjustment
downward.7 Finally, as with all agents, side effects should be considered. For azoles in particular,
increases in transaminases may occur, and typically will regardless of azole agent selected. Monitoring
these changes is very important.
This retrospective analysis sought to characterize the use of voriconazole and itraconazole in a
group of pediatric patients admitted to UNC Medical Center. The primary objective was to serve as a
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hypothesis-generating project for future studies while describing the indications, dose, duration, side
effects, and drug interactions for these two azole agents.
Methods
Study Design:
This study was a retrospective single-center cohort study and chart review of pediatric patients admitted
to UNC Medical Center. This project largely served as a hypothesis-generating project for future studies,
while initially characterizing the use of itraconazole and voriconazole in a subset of pediatric patients.
Patients were identified using Siemens Pharmacy System and medical records were viewed using Webcis.
All information collected from Webcis was compiled in Excel. Descriptive statistics were used to analyze
the data collected. The University of North Carolina at Chapel Hill Institutional Review Board approved
all study procedures.
Participants:
Patients were < 18 years old and were admitted to UNC Hospitals between October 2012 and March
2014. All patients were receiving intravenous or oral voriconazole or oral itraconazole as prophylaxis or
for treatment of invasive fungal infections during their admission, with only the first admission being
utilized for data collection purposes.
Study Outcomes:
Demographic information collected include age, sex, race, and weight. Other information collected
included diagnoses, antifungal agent used, indication, dose, duration, serum concentrations, culture
results, interacting therapies, and lab values, specifically AST and ALT as well as white blood cell count.
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Results
A total of 37 patients were included in this retrospective study. The study population included
51% males (N=19) with a mean age of 10.3 years. Within this group of patients, 54% were white, 35%
were black, and 11% were classified as “other”. Significantly more of these patients were
immunosuppressed due to chemotherapy (62%) though 35% of these 37 patients did have cystic fibrosis.
The use of the antifungal agent was fairly evenly split between prophylaxis (43%) and treatment (57%).
Positive aspergillus cultures was present in 27% (N=10), and Candida in 14% (N=5) culture results.
Thirty percent of cultures were reported as no growth (N=11). Cultures were obtained largely from
sputum samples (35%) but also blood (19%) and other sites like nasal swabs and urine (16%).
Voriconazole was used in 73% of patients and itraconazole in the remaining 27% of patients.
For patients on voriconazole (N=27), dosing ranged from 5 mg/kg/day to more than 12
mg/kg/day. While 22% of patients (N=6) were on an initial dose of 5-8 mg/kg/day, this dropped to 15%
(N=4) of patients for the final dose. Five percent of patients were on a dose of 9-12 mg/kg/day for both
initial and final dose. For the higher doses of more than 12 mg/kg/day, 15% of patients were on this
initially and 22% of patients had a final dose in this range. For those patients on itraconazole (N=10), no
patients were on an initial dose of 5-8 mg/kg/day initially but two patients (20%) were on a final dose in
this range. Two patients (20%) were on a dose of 9-12 mg/kg/day initially but four patients (40%) were
on a final dose in this range. For the highest dose range of more than 12 mg/kg/day, five patients (50%)
were on this dose initially but none were on a final dose in this range. In terms of dose changes, the
majority of patients (60%) did not have an initial or final dose to assess increasing or decreasing dose
over time, though 5% of patients in this sample did have an increased dose and 35% had no change in
dose. Duration of antifungal therapy varied, with 60% (N=22) of patients on this therapy for less than 2
weeks, while 19% (N=7) were on it for two to four weeks, 5% (N=2) for four to six weeks, and 14%
(N=5) for more than 6 weeks, usually indefinitely.
Therapeutic drug monitoring was not reported in the majority of cases (N=32) but for four cases,
levels of either voriconazole or itraconazole were reported as therapeutic and for one case as not
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therapeutic. Interacting medications recorded in patient profiles were cyclosporine, with an incidence of
two, and tacrolimus, which was seen three times in this sample.
Lab changes, specifically white blood cell (WBC) count, AST and ALT changes, were recorded
as well. WBC increases occurred in 32% of patients, decreases in 49% of patients, and 19% had no
information from which to draw a conclusion of increase or decrease. In 22% of patients, AST increased,
while it decreased for 35% of patients and there was insufficient information in 43% of patients. ALT
increased in 30% of patients, decreased in 30% of patients, showed no change in 3% of patients, and there
was insufficient information to draw a conclusion in 38% of patients.
Table 2. Demographic data.
Age
Male sex
Ethnicity
White
Black
Other
Cystic fibrosis
Immunosuppressed
Indication
Prophylaxis
Treatment
Organism
Aspergillus
Candida
No growth
Culture site
Blood
Sputum
Other
Baseline Demographics (N=37)
10.3 ± 5.4
19 (51%)
20 (54%)
4 (11%)
13 (35%)
13 (35%)
23 (62%)
16 (43%)
21 (57%)
10 (27%)
5 (14%)
11 (30%)
7 (19%)
13 (35%)
6 (16%)
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Table 3. Initial and final dosing ranges.
Voriconazole (N=27)
5-8 mg/kg/day
9-12 mg/kg/day
> 12 mg/kg/day
Itraconazole (N=10)
5-8 mg/kg/day
9-12 mg/kg/day
>12 mg/kg/day
Initial Dose (n,%)
6 (22%)
2 (5%)
4 (15%)
Initial (n, %)
0
2 (20%)
5 (50%)
Final Dose (n,%)
4 (15%)
2 (5%)
6 (22%)
Final (n, %)
2 (20%)
4 (40%)
0
Discussion
In this retrospective study, the indication for use of voriconazole or itraconazole included both
prophylaxis and treatment with dosing covering a broad range and no consistent trends for dose changes.
Aspergillus was more common than Candida, and though most samples were sputum other sites were
selected as well. Therapeutic drug monitoring was inconsistent, and levels were reported as therapeutic or
not therapeutic, without direct values, when they were reported. Lab values like AST or ALT and WBC
did not show consistent trends with antifungal therapy. Due to this being largely a hypothesis generating
project, no definitive conclusions may be drawn about the direct relationship between factors like dose or
duration of therapy and efficacy and safety outcomes. However, the information collected may be used to
formulate more definitive study designs for the future in the pediatric population.
Based on the data collected, patients in this sample illustrated the same tendency at the Johns
Hopkins study to grow Aspergillus more frequently than other previously more common organisms like
Candida. It would also appear that voriconazole, possibly due to its better bioavailability, is more often
prescribed for prophylaxis and treatment than itraconazole at UNC Medical Center. Dosing ranges were
broad and inconsistent as to increases or decreases, and with so many patients not having a final or initial
value recorded it is difficult to make a definitive conclusion as to if the tendency was to become more
aggressive with dosing further into treatment or to deescalate dosing with time. Lab values did not appear
to correlate with the expected trends during treatment with azoles but the lack of data in some patients
may be responsible for this.
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The limitations of this study highlight some of the difficulties in pediatric research. Using Webcis
to collect data proved to be a challenge largely due to the narrative format of recording patient notes. At
the time the study was performed, Webcis was in an archived format and much of the functionality had
been lost. As a result, finding information easily such as dose changes and levels drawn was difficult.
There was also no standardized place to put some of this information which could explain why for some
patients lab values, dose changes, and duration of therapy is missing. As previously noted, many of either
the initial or final values for labs or dosing were missing and as a result very few conclusions can be
drawn from this information. With the change to EPIC as a system for recording this information at UNC
Medical Center, this problem will hopefully be relieved in future studies. .
This study highlighted how much is still unknown about the use of antifungals in pediatric
patients, whether in their dosing, drug interactions, or monitoring parameters, largely due to a lack of data
available and smaller populations to assess. By instituting a more firm set of parameters for monitoring, it
may be possible to generate more specific conclusions about drug interactions, dose, duration, and
individual levels of antifungals such as voriconazole and itraconazole in the pediatric population. As a
result, some conclusions about efficacy and safety may be made in the future so the appropriate dosing is
utilized for both prophylaxis and treatment indications.
Limitations in this data collection and others previously may be remedied by better systems to
pull data from as well as an increasing number of studies initiated. The ultimate goal is to establish a wellresearched dosing and monitoring set of parameters in pediatrics that is both efficacious and safe.
Anna Cosnahan
References
1. Ozsevik SN, Sensoy G, Karli A, et al. Invasive fungal infections in children with hematologic and
malignant disease. J Pediatr Hematol ONcol 2015; 37:e69-e72.
2. Muller F and Seidler M. Characteristics of pathogenic fungi and antifungal therapy in cystic
fibrosis. Expert Rev Anti Infect Ther 2010; 8(8):957-964.
3. Valerio C, Perillo T, Brescia L et al. Antifungal agents in current pediatric practice. Curr Infect
Dis Rep 2013; 15: 278-287.
4. Pana Z, Kougia V, and Roilides E. Therapeutic strategies for invasive fungal infections in
neonatal and pediatric patients: an update. Expert Opin Pharmacother 2015; 16(5):693-710.
5. Cecinati V, Guastadisegni C, Russo FG, et al. Antifungal therapy in children: an update. Eur J
Pediatr 2013; 172:437-446.
6. Lestner JM, Smith PB, Cohen-Wolkowiez M, et al. Antifungal agents and therapy for infants and
children with invasive fungal infections: a pharmacological perspective. Br J Clin Pharmacol
2012; 75(6):1381-1395.
7. Azuk FM, Tezer H, Parlakay AO, et al. Secondary antifungal prophylaxis in pediatric
hematopoietic stem cell transplants. J Pediatr Hemaol Oncol 2015; 37:e19-e22.