Off-label antibiotic use in a specialized children care hospital in Punjab, Pakistan: Findings and implications

Introduction: Most of the antibiotics currently used in pediatrics are either unlicensed or being prescribed outside the specifications of product label (off-label prescribing). The aim of this study was to assess the extent of off-label antibiotic use in pediatrics. Methodology: A six month longitudinal off-label antibiotic utilization survey was carried out from January to June, 2018. A structured questionnaire was designed to collect detailed information for each pediatric patient admitted to participating health center. The data included basic demographic and clinical diagnosis with details of prescribed antibiotics (formulation, dose, dosage, route of administration and indication for use). Data were analyzed using Social packages for Statistical Sciences (SPSS) version 21.0. Results: Of 1,810 admissions, 1,795 (99.2%) patients received antibiotics. Out of these, a total of 451 (25.1%) patients (326 patients admitted in the medical ward and 125 patients in ICUs) received at least one unlicensed/off-label antibiotic. Antibiotics were predominantly prescribed for the treatment of infections (n = 311, 69.0%). The majority of the pediatric patients who received off-label antibiotic suffered from respiratory tract infections (n = 223, 49.4%), skin and soft tissue infections (n = 53, 11.8%), gastrointestinal tract infections (n = 56, 12.4%) and other infections (n = 46, 10.2%). Co-amoxiclav (n = 190, 42.1%) was the most frequently off-label prescribed antibiotic to pediatric patients. An inappropriate dose for patients (n = 430, 95.3%) was the most frequent cause of prescribing off-label antibiotics. Conclusions: Further evaluation of health and economic outcomes of off-label prescribing and determinants influencing the drug choice is required.


Introduction
Rational drug use in the pediatric population is a major concern around the globe for clinicians and regulatory organizations due to the paucity of evidencebased literature on safety and efficacy of antibiotics in pediatrics. Most of the drugs prescribed to pediatrics are utilized outside the specifications of licensed drug which include the indication, dose, route of administration, and age groups of patients [1][2][3][4]. Use of off-label/unlicensed drugs in the pediatric population is widespread that mainly occurs in medical and surgical wards as well as in intensive care units (ICUs) [2,5]. Use of off-label drugs gives rise to inconsiderable adverse drug event that requires hospitalization and additional therapies [6][7][8][9]. The European community has introduced the guidelines on clinical investigation of drugs in pediatrics that is considered as positive approach related to encouragement of clinical trials for conditions in pediatrics [10,11]. Despite these guidelines, there are certain barriers where pharmaceutical industries may have been resistant to conduct clinical trials in pediatrics. These barriers include ethical conflicts, issues with blood sampling, and problems in enlisting the adequate number of children [1]. The most commonly prescribed off-label drugs in pediatrics are antibiotics [12].
Infections have always been a prime issue in pediatrics with substantial morbidity and mortality [13]. Most of the medications including essential drugs are not tested and approved for use in children which may lead to medication errors. Several studies documented that medication errors are 3 times more frequent in children than adults [14]. A study reported higher mortality rates in neonates who received a combination of sulphisoxazole and penicillin than those who received oxytetracycline [15]. A higher incidence rate of kernicterus has been reported in pediatrics receiving sulphonamide (highly protein bound drug that results in the displacement of bilirubin from albumin) and penicillin [16]. Data on adults cannot be supposed to anticipate the adverse events of drugs in pediatrics [17]. Drug metabolism in children may show differences with respect to that in adults. An altered metabolism of chloramphenicol results in grey baby syndrome in the newborn or infant in which cyanosis, vomiting, cardiorespiratory failure and abdominal distention are developed [18]. Reduction of the dose of chloramphenicol may result in the prevention of the development of grey baby syndrome [19]. Tetracycline if given in pregnancy or to pediatrics under age of eight years, it can cause harm to teeth and bones [1]. In order to reduce drug toxicity, it is essential to understand the correlation between drug metabolism and age [1]. Many literatures have been published worldwide regarding off-label/unlicensed drug use in pediatric population.
However, in Pakistan, there is scarcity of data on the pattern and magnitude of off-label/unlicensed antibiotic use in pediatrics [20,21]. Therefore, the aim of the present study was to assess the extent of offlabel/unlicensed antibiotic use in pediatrics.

Study design
A six month longitudinal off-label antibiotic utilization survey was carried out from January to June, 2018 in a pediatric hospital in public sector receiving patients from Punjab. The Children's Hospital and Institute of Child Health Lahore is one of the largest public private children hospital in Pakistan that provides both inpatient and outpatient services with all possible diagnostic facilities. The total bed strength has been reached to 1,050. Antibiotic containing prescriptions were assessed for all inpatients admitted in general medical wards, intensive care units, neonatal units and pediatric medical wards of the hospital in Lahore, Pakistan. The study was approved by Human Ethical Committee of University College of Pharmacy, Punjab University, Lahore (HEC/PUCP/1,954) and Ethical Review Board of The Children's Hospital and Institute of Child Health Lahore (8,227). Parents or legal guardians were informed about the aim of the survey and written consent was taken from them.

Data Collection
A written prescription for all inpatients pediatrics under the age of 12 was collected during the study period. The age-groups of the pediatric were divided into neonates (birth to 1 month), infants (1 month to 2 years) and children (2 to 12 years). We used two types of variables including socio-demographic characteristics and clinical characteristics and current medical history to evaluate the prescribed drug (brand name, generic name, indication, dose, frequency and route of administration). We excluded the prescriptions containing a drug that did not require a license. When required, additional data were extracted from wards nurses and prescribing healthcare practitioners regarding drug information during hospitalization. The data included age, gender, weight, and clinical diagnosis with the details of prescribed antibiotics (formulation, dose, dosage, route of administration and indication for use).
Off-label antibiotic use was evaluated on the basis of data mentioned in British National Formulary and on the leaflet of the product as well as information which could be obtained from pharmaceutical companies [22]. The off-label use was defined as the drug which was administered for an unapproved indication or in an unapproved age group, dose, frequency and route of administration [23]. Some drugs were considered offlabel with more than one reasons.

Statistical Analysis
Final data were analyzed using Social Packages for Statistical Sciences (SPSS) version 21.0. The frequencies and percentages were used to indicate the demographic characteristics and drug-related variables.

Results
The number of patients hospitalized during the study period was 1,810. Of 1,810 admissions, 1795 patients received antibiotics. The study involved a total of 451 patients (326 patients admitted in the medical ward and 125 patients in ICUs) who received at least one unlicensed/off-label drug. Majority of the patients were males (n = 298, 66.1%) ( Table 1). The extent of off-label prescribing was higher in infants (42.1%) than in neonates and children ≥ 2 years. Antibiotics were predominantly prescribed for the treatment of infections (n = 311, 69.0%). A total of 279 patients received antibiotics for community-acquired infection (CAP) and 31 patients for hospital-acquired infections. About 122 patients received antibiotics for medical prophylaxis, followed by surgical prophylaxis (n = 15, 3.3%). Majority of the patients suffered from respiratory tract infections (n = 223, 49.4%), skin and soft tissue infections (n = 53, 11.8%), gastrointestinal tract infections (n = 56, 12.4%) and other infections (n = 46, 10.2%) ( Table 1).

Discussion
Over the past few years, multisite studies have been carried out that clearly indicated the frequent use of the off-label antibiotics in pediatrics, particularly among neonates [24,25]. To the best of our knowledge, this is the first study conducted in Pakistan to assess the nature and magnitude of off-label antibiotics use in overall pediatric population. Based on our findings, the overall prevalence of the prescription of off-label drug was 25.1%, which was similar to that in Germany (36%) and Netherlands (44%) [25,26]. The off-label/unlicensed drug was frequently prescribed to males than females. Our findings reported that the higher prevalence rate of the prescribed off-label drug was observed among infants. However, several studies reported that the magnitude of off-label prescribing was accounted to be between 15.0% and 60.0% in infants and 90.0% in neonates [1,27,28].
Co-amoxiclav, ceftriaxone, and ciprofloxacin were frequently used as an off-label/unlicensed drug. This finding was different when compared to the other study conducted in Ethiopia which reported ceftriaxone, cloxacillin, and gentamicin as the commonly used offlabel antibiotic used [29]. Ciprofloxacin was frequently used as the off-label drug among neonates. Quinolones are not recommended for use in pediatrics but several studies on quinolones have clearly revealed that they can be administered to pediatrics with maximum therapeutic effect and minimum or no significant toxicity [30,31]. The most frequent condition of prescribing off-label antibiotic use in our study was inappropriate dosing. Several studies reported similar outputs conducted in different regions of the world [1,12,25,32]. Inappropriate dosing is of major concern for antibiotic use regarding the development of resistance [33,34]. If the drug is under dosed, there may be no therapeutic effect but may cause a risk of adverse drug reactions.
Despite the widespread use of the offlabel/unlicensed drug, the significance of drug safety and efficacy in children has been acquiring less attention in the developing countries [27,29,35]. Lack of harmonization between authorized drug label and pediatric documentation in evidence-based literature which affects the prescribing behavior of physicians could be the main reason of the use of offlabel/unlicensed drug in the pediatric population [29]. Expert groups fully dedicated to pediatric drug treatment are required within the administration of the drug and therapeutic committees, which could formulate new data and deliver the relevant data to prescribing physicians [29]. World Health Organization (WHO) adopted "Better Medicine For Children" that not only highlights its major concern on offlabel/unlicensed drug but also improves drug safety and efficacy in the pediatric population [36]. In order to ensure quality information on safety and efficacy for the various pediatric drugs, the strict drug approval procedure should be followed.
The current study has some limitations because it was carried out only in one hospital and the sample size was relatively small. Therefore, the results evaluated concerning off-label antibiotic use may not be representative of patients outside the hospital. Lack of pharmacist role in Pakistan, may be a reason for the irrational use of antibiotics. Therefore, there is a need to evaluate the situation at general practitioners (GP) level.

Conclusion
Despite the frequent use of the off-label/unlicensed drug in pediatrics, our findings demonstrate that offlabel prescribing accounted for 25.1%. The main contributor to off-label prescribing is an inappropriate dose which may predispose the children to the occurrence of side effects without a therapeutic effect and promotes the development of antibiotic resistance. Implementation of the evidence-based approach in prescribing antibiotics by formulating more quality literature on the safety and efficacy of off-label drug would improve the appropriate use of antibiotics in the pediatric population. More studies are required to investigate the situation at a national level. Further evaluation of public and economic healthcare outcomes of off-label prescribing and determinants influencing drug choice is required.