Aims & Objectives:

 The aims & objectives of this study are –

In the patients admitted to the Pediatric intensive care unit (PICU) -

1.     To study the utilization of systemic antifungal drugs, as per the WHO International Network for Rational Use of Drugs (INRUD) indicators.

2.     To study the indications for systemic antifungal therapy (empirical/definitive).

3.     To study "Off-label" use of antifungal drugs.

4.     To study the outcome (survival/ death) in patients who receive systemic anti-fungal drug therapy. 

 Materials & Methods:

Ethics

The study will be initiated after seeking approval from the "Institutional Ethics Committee (IEC)" of Seth G.S. Medical College and KEM hospital. The study will be conducted in compliance with the "Ethical Guidelines for Biomedical Research on Human Participants" by the Indian Council of Medical Research (ICMR).

Consent & assent

Case enrolment will be done after a written informed consent from the parent/ guardian. Assent will be obtained from patients more than 7 years of age. Since patients in the PICU are critically ill, the assent will be procured from children aged 7 years and above once the clinical condition stabilizes and when they are in a position to give the assent.

Study site

The study will be conducted in patients admitted to the PICU of KEM hospital, Mumbai, which is a tertiary care, 14-bedded PICU with state-of-art facilities including mechanical ventilators, non-invasive monitors and other devices for delivering critical care. It is manned by at least 4 resident medical Officers round the clock. One Professor looks after the day-to-day clinical and administrative matters of the PICU and is assisted by one Associate Professor and one Assistant Professor. Fellows (MUHS) and senior registrars are also posted in the PICU (when available).

Study design 

A prospective, descriptive, non-interventional, single center study comprising of data collected over a period of one year.

Study period (study duration)

The study will be conducted over 1 year after approval from IEC or till the desired sample size is reached. Patients will be recruited over a period of one year. Each patient will be in the study till his/ her stay in the PICU.

Confidentiality

The participant’s details will not be disclosed at any point of time.

Sample size calculation

All consecutive patients admitted to the PICU and treated with systemic antifungal drug/s will be enrolled over a period of one year. As observed from the PICU records, about 20% PICU patients (out of approximately 400 annual admissions) are started on antifungal agents. Expected sample size of the patients treated with systemic antifungal drugs will be 20/100×400= 80. Therefore, 80 patients will be enrolled in this study. This is a convenience sampling; hence no formal sample size calculations have been done.

 Inclusion Criteria

All patients in the age group of >28 days to up-to 12 years, who are admitted to the PICU and treated with systemic antifungal drugs (either newly started on antifungal drugs or already on antifungal drugs) will be enrolled in the study.

Exclusion criteria

Patients whose parent/ guardian refuse to give informed consent, will be excluded from the study.

WHO Core Drug Use Indicators:^6,12

Prescribing indicators:

1.     Average number of medicines prescribed per patient encounter.

2.     Percent medicines prescribed by generic name.

3.     Percent encounters with an antibiotic prescribed.

4.     Percent encounters with an injection prescribed.

5.     Percent medicines prescribed from essential medicines list or formulary.

Facility care indicators:

1.     1.Availability of essential medicines list or formulary to practitioners.

2.    2. Percent key medicines available.

Study Procedure & Data Recording

All consecutive patients admitted to the PICU satisfying the inclusion criteria will be enrolled after obtaining informed consent from the parent/ guardian. Prospective data will be recorded from indoor case sheets/ papers.

Data Recording: Following data/information will be recorded in a pre-designed case record form- CRF (from the patient’s hospital case sheets/indoor medical papers)-

·       Demographic details: name (initials), age (in months), sex, date of admission to the hospital, date of admission to the PICU, date of discharge from the PICU/death and date of discharge from hospital.

·       Primary system involved, complete diagnosis and risk factors for systemic fungal infections will be noted.

·       Indication for use of systemic antifungal drugs:¹³ Antifungal drugs are used in PICU either empirically or as definitive use-

Empirical Treatment: Empirical treatment is defined as use of antifungal drug/s in treatment of patients who have suspected fungal infection.

Definitive Treatment: Definitive treatment defined as use of antifungal drug/s after microbiological evidence of fungal infection or after other diagnostic confirmation.

·       Outcome related data: Final outcome of the patient (survival/ death), length of PICU stay and length of hospital stay will be noted.

·       “Off-label” use:

The term “Off-label” use refers to the use of a drug that is not included in the package insert for that drug or the use outside of its accredited product license, as defined in the Summary of Product Characteristics (SmPC).¹⁴ The drug use will be considered “Off-label” if it satisfies one or more of the following 6 criteria.^15,16

1.     Age: Drug not recommended in the SmPC under a certain age

2.     Weight: Drug not recommended in the SmPC under a certain weight

3.     Route of administration: Drug not recommended in the SmPC under a certain route

4.     Absence of pediatric information: No mention in SmPC concerning pediatric use

5.     Dose: Dose higher than SmPC recommendations

6.     Indication: Drug prescribed for indications outside of those enumerated in the SmPC

T       The patient’s daily medical records will be scrutinized from admission until discharge/ death. All investigations done routinely in the PICU as a part of the treatment protocol will be recorded in the CRF. This study will not entail performing any new/ additional investigations 

This will aid in allocating appropriate resources for effective diagnostic and therapeutic interventions for fungal infections in the PICU, thus enabling the provision of optimal medical care to the patients in the future.

13. Pana ZD, Kougia V, Roilides E. Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients: an update. Expert Opin Pharmacother 2015 ;16:693-710.

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 20. Dinleyici EC. Pediatric invasive fungal infections: realities, challenges, concerns, myths and hopes. Expert Rev Anti Infect Ther 2011;9:273-274.

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22. Patel GP, Simon D, Scheetz M, Crank CW, Lodise T, Patel N et al. The effect of time to antifungal therapy on mortality in Candidemia associated septic shock. Am J Ther 2009;16:508-511.

23.Singhi S, Deep A. Invasive candidiasis in pediatric intensive care units. Indian J Pediatr. 2009 ;76:1033-44.

24. Singh N. Changing spectrum of invasive candidiasis and its therapeutic implications. Clinical Microbiology and Infection 2001;7:1-7.

25.Czarniak P, Bint L, Favié L, Parsons R, Hughes J, Sunderland B. Clinical setting influences Off-label and unlicensed prescribing in a paediatric teaching hospital. PLoS One 2015 10;10:e0120630.

26.Lass-Flörl C. Triazole antifungal agents in invasive fungal infections: a comparative review. Drugs 2011 24;71:2405-19.