Antifungal Prophylaxis With Posaconazole in Immunocompromised Children Younger Than 13 Years

The use of prophylactic antifungals has decreased the risk of the development of invasive fungal infections (IFIs) in cancer patients and patients undergoing HSCT, which is a major cause of morbidity and mortality.^1,2 

Posaconazole is an extended-spectrum triazole used primarily for the prophylaxis and treatment of IFIs refractory to other antifungal therapies, owing to its extensive coverage of yeast and filamentous fungi, and has been shown to be effective in adolescents and adults.^2–4  This drug is only approved for use in adults in Europe, and the oral suspension is approved by the FDA only in individuals older than 13 years.^3,4  The recommendation for the use of posaconazole in children younger than 13 years is limited to individual cases as an “off- label” prescription.⁵ 

Therefore, the use of PP in children has not been fully evaluated, and this is important because the underlying risk of drug toxicity and poor adherence to the drug could impact the failure of prophylaxis, increasing the risk of breakthrough fungal infection.^3–5  Nonetheless, while the efficacy, safety, and pharmacokinetic characteristics of posaconazole as a prophylactic alternative have been evaluated in high-risk pediatric patients, such as in acute myeloid leukemia, recurrent acute leukemia, and allogeneic HSCT,^6,7  it is only recommended for use in patients older than 13 years, unlike other antifungal drugs such as fluconazole, itraconazole, and voriconazole.^6,7 

In 2016, the Pan American Health Organization held in Lima, Peru, the first regional meeting on antimicrobial resistance for the development and implementation of national strategies and action plans on antimicrobial resistance in Latin American countries.⁸  Since August 2017, the Instituto Nacional de Salud del Niño San Borja (INSN-SB) has progressively implemented an antimicrobial stewardship program, which consists of 2 phases: phase 1 was directed to antibiotics and later phase 2 incorporated antifungal agents. The data presented in this article correspond to patients treated since 2014.

The aim of this study was to describe our experience with PP in children younger than 13 years with hemato-logic diseases, with and without HSCT, at the INSN-SB in Lima, Peru.

Setting. The INSN-SB is a pediatric referral hospital located in Lima, Peru, which provides care for children and adolescents with hematologic diseases, including patients undergoing HSCT. The Department of Clinical Hematology has 24 beds and a transplant unit with 20 beds.

Study Design, Study Population, and Selection Criteria. Retrospective review of the medical charts of patients. From January 2014 to December 2018, all patients treated in our institution, younger than 13 years and with hematologic diseases, with and without HSCT, and receiving antifungal PP were included in the study. Patients with incomplete data for the variables analyzed in the medical record were excluded.

Study Variables. Demographic variables such as age, sex, underlying oncologic or hematologic disease, reception of HSCT, and development of graft-versus-host disease (GvHD) were recorded. Each course of PP was defined by time of prophylaxis prescription; when a patient had no indication of PP for 2 weeks, this was considered as cessation of the prophylaxis course.

Variables associated with toxicity and the effectiveness of PP were also registered, including the prophylactic dose used, concomitant use of proton pump inhibitors (PPIs), presence of mucositis, side effects (while using PP), liver enzyme values—alanine aminotransferase (ALT) and aspartate aminotransferase (AST)—and the history and development of new fungal infection during antifungal prophylaxis (breakthrough fungal infection). To establish the differences in the values of the liver function tests with the use of posaconazole, 3 periods were determined: before the indication of prophylaxis, during prophylaxis, and after the discontinuation of prophylaxis. To determine and classify IFIs as possible, probable, and proven, the diagnostic criteria of the European Organization for Research and Treatment of Cancer and Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (EORTC/MSG) were used.⁹  No data regarding posaconazole plasma concentrations were collected because the test was not available at the institution during the data collection period.

Data Analysis. Descriptive statistics of variables were expressed as medians and IQR, according to the analysis of the distribution of data, while qualitative variables were summarized by using frequency and percentages. For the overall analysis of the 3 periods the Kruskal-Wallis and Mann-Whitney U tests were used to determine differences between 2 periods (before vs during, during vs after, and before vs after). The Stata version 16 statistical software (Stata Corporation, College Station, TX) was used for the analyses. A value of p < 0.05 was considered statistically significant.

Fifty-six courses of PP were identified in 47 patients; of these, 5 patients received more than 1 course of PP. The baseline characteristics of patients with PP are shown in Table 1. The median dose of posaconazole used was 13.6 mg/kg/day (IQR, 12–16.8). The median duration of PP was 24 days (IQR, 16–82), with 33.9% concomitantly using PPIs while 7.14% had mucositis. The median absolute neutrophil count before the beginning of PP was 600 cells/mL (IQR, 150–1980). Side effects found during the use of PP are described in Table 2.

An increase in the mean values of liver function tests during the administration of PP is observed for both ALT (33.5 vs 70 U/L; p < 0.001) and AST (30 vs 59 U/L, p < 0.001) in comparison to the mean values of the liver tests before prophylaxis. Likewise, a decrease in liver function test values to normal values is observed after discontinuation of antifungal prophylaxis, both for ALT (70 vs 39 U/L; p < 0.001) and for AST (59 vs 31.5 U/L, p < 0.001) (Figure).

We identified 5 breakthrough fungal infections on the basis of antifungal prophylaxis courses: 4 cases of invasive aspergillosis (2 probable and 2 possible), and 1 case of invasive candidiasis. Of the total patients, 15 (31.91%) had a prior history of IFIs (11 invasive aspergillosis and 4 invasive candidiasis). Table 3 shows the characteristics of the cases presenting breakthrough fungal infections.

In our study, breakthrough fungal infection, increased transaminase values, and gastrointestinal symptoms were observed during PP in children younger than 13 years. Oral posaconazole is an alternative “off-label” medication for patients younger than 13 years. However, there are concerns related to the bioavailability of the drug, which may be variable, making it difficult to achieve optimal plasma concentrations of posaconazole in pediatric patients, even with an adequate dose regimen.¹¹  Our patients received dosing schemes similar to those reported in previous studies (12 mg/kg/day),^11,12  with the variations observed in our institution being due to a non-standardized prescription regimen during the study period. On the other hand, a previous study demonstrated that doses lower than 12 mg/kg/day could be related to suboptimal posaconazole plasma concentrations (values lower than 0.7 μg/mL).¹³  Another study, which administered oral posaconazole to pediatric patients, found that giving 3 times daily regimen was more likely to achieve an optimal mean concentration, between 500 and 2500 ng/mL.⁷ 

In this regard, some authors suggest an increase in the frequency of the dose interval to achieve optimal plasma concentrations owing to the saturable bioavailability of posaconazole.¹⁴  An initial dose of PP of 200 mg 3 times daily (oral suspension) is recommended in pediatric populations between 6 months to 6 years of age, while in children between 7 and 12 years of age, 300 mg 3 times daily, increasing the dose if the trough is lower than 0.7 mg/L.¹⁴ 

Other factors can affect the absorption of posaconazole, such as the concomitant use of PPIs and the presence of mucositis, which limit the achievement of optimal prophylactic and therapeutic concentrations.^15,16  One study reported that the use of PPIs was associated with a 42% reduction in posaconazole bioavailability in children younger than 13 years.¹⁴  In our study, a third of patients with PP used PPIs, owing to limited supervision of prescriptions during the initial stages of antimicrobial stewardship program implementation. The bioavailability of posaconazole was not analyzed in this study; therefore, it is not possible to evaluate the effect of the use of PPIs. However, other studies found that higher gastric pH decreases the plasma concentration of posaconazole, secondary to the use of PPIs, but this was not observed with the use of H2 receptor antagonists.¹⁷ 

Concerning possible side effects due to the use of posaconazole, several studies have described clinical findings similar to ours, corresponding mainly to gastrointestinal manifestations such as abdominal pain and nausea.^11,12,18  On the other hand, the 2- to 3-fold increase in ALT and AST values observed in our study has also been described in other studies on PP in children.^18,19  In addition, comparative studies of different groups of azoles, including posaconazole, described similar side effects, reporting a significant increase in ALT and AST values during antifungal prophylaxis. ^11,12 

We found a higher number of breakthrough fungal infection cases (5 cases; 8.9%); it should be noted that patients in 3 of these cases concomitantly used PPIs, 2 did not receive the drug along with high-fat meals, and 1 had mucositis. Other studies observed only 1 case of breakthrough fungal infection by Aspergillus fumigatus (3.0%) in patients younger than 18 years during PP,¹⁹  with other series in children reporting no case of breakthrough fungal infection during PP.^6,18  In a study comparing itraconazole, voriconazole, and posaconazole used as oral antifungal prophylaxis in pediatric patients undergoing HSCT, no case of breakthrough fungal infection was found in the posaconazole group, while in the itraconazole and voriconazole groups there were 4% and 6% of possible cases of IFIs, respectively.¹² 

In patients younger than 13 years, the main prophylactic antifungal agents (with activity against filamentous fungi) recommended are itraconazole and voriconazole with the use of therapeutic drug monitoring (TDM), in both cases.^3,20  Posaconazole is an “off-label” alternative in this group of patients, and it also requires TDM, especially when used in oral suspension and in children younger than 13 years.²¹  Wass et al²²  demonstrated that in pediatric patients, the use of posaconazole oral suspension was less effective in achieving therapeutic serum concentrations than the delayed-release tablets.

The clinical and laboratory findings in our study may be due not only to the use of posaconazole, but also to the use of another medication or interaction with other drugs used in this group of patients. Furthermore, TDM of posaconazole was not performed and therefore a relationship between the side effects observed (clinical, laboratory, and breakthrough fungal infection) and the plasma concentrations of the drug (supratherapeutic or infratherapeutic) could not be determined.

In conclusion, patients younger than 13 years who received PP showed an increase in transaminase values, and the development of breakthrough fungal infections, demonstrating the need for TDM during this type of prophylactic treatment.

ALT

alanine aminotransferase

AST

aspartate aminotransferase

EORTC/MSG

European Organization for Research and Treatment of Cancer and Mycoses Study Group of the National Institute of Allergy and Infectious Diseases

FDA

US Food and Drug Administration

GvHD

graft-versus-host disease

HSCT

hematopoietic stem cell transplant

IFI

invasive fungal infection

INSN-SB

Instituto Nacional de Salud del Niño San Borja

PP

prophylaxis with posaconazole

PPI

proton pump inhibitor

TDM

therapeutic drug monitoring

The authors thank Dr Carlos Ramírez Vallejos for his collaboration in the study.