Drug Therapy Problem and its Contributing Factors among Pediatric patients with Infectious Diseases admitted to Jimma University Medical Center, South West Ethiopia: Prospective observational study

Background: Drug therapy problem is a significant challenge to provide high quality health care service for the patients. It is associated with morbidity, mortality, increased hospital stay and reduced quality of life. Moreover, pediatric patients are quite susceptible to drug therapy problems.Thus this study aimed to assess drug therapy problem and its contributing factors among pediatric patients diagnosed with infectious disease admitted to pediatric ward of Jimma university medical center, from April ,2018 to June 30, 2018. Methodology: Prospective observational study was conducted among pediatric patients with infectious disease admitted to Jimma university medical center from April 01,2018 to June 30, 2018. Drug therapy problems were identified by using Cipolle’s and strand’s drug therapy problem classification method. Patient’s written informed consent was obtained after explaining the purpose of the study. Patient’s specific data were collected using structured questionnaire. Data was entered into Epi data version 4.0.2 and then exported to statistical software package version 21.0 for analysis. To identify predictors of drug therapy problems occurrence, multiple stepwise backward logistic regression analysis were done. The 95% CI was used to show the accuracy of data analysis and statistical significance was considered at p-value <0.05. Results: A total of 304 pediatric patients were included in the study. Of these, 226(74.3%) patients had at least one drug therapy problem during their hospital stay. A total of 356 drug therapy problems were identified among two hundred twenty six patients. Non-compliance (28.65%) and dose too low (27.53%) were the most common type of drug therapy problems while disease comorbidity AOR=3.39, 95% CI= (1.89-6.08), Polypharmacy AOR=3.16, 95% CI= (1.61-6.20) and more than six days stay in hospital [AOR=3.37, 95% CI= (1.71-6.64) were independent predictors of drug therapy problem occurrence. Conclusion and recommendation: Drug therapy problems were common in pediatric patients with infectious disease in the study area. Presence of comorbidity, Polypharmacy and Prolonged hospital stay were the predictors of drug therapy problem in this finding. Therefore, to overcome the significant gaps in pediatric pharmaceutical care, clinical pharmacists, Pediatricians and other health care professional have to work in collaboration.

area. Presence of comorbidity, Polypharmacy and Prolonged hospital stay were the predictors of drug therapy problem in this finding. Therefore, to overcome the significant gaps in pediatric pharmaceutical care, clinical pharmacists, Pediatricians and other health care professional have to work in collaboration. Keywords: Drug therapy problem, Pediatric, infectious disease, Ethiopia Background Pediatrics are special population those younger than 18 years old. They differ from adults and within their age groups in body surface area, weight, and organ function development which affect the efficacy and safety of pharmacotherapy (1,2). The immunity of the children is not well developed. This enable them vulnerable to serious and potentially lethal infectious disease (3).
Infectious disease is one of the most common medical problems of pediatric population in developing countries. As reported findings showed in sub-saharan African such as Egypt (4) and Ethiopia (5) about 70-86.4% of infectious diseases were diagnosed among children. The most common infectious diseases identified among these children were sepsis, pneumonia, meningitis, malaria, acute gastroenteritis, upper respiratory tract infection and intestinal parasites. Therefore; antimicrobials such as penicillin G crystalline, gentamicin, ceftriaxone and ampicillin were routinely prescribed for managing these infectious diseases (6).
Antimicrobials are a cornerstone to treat infectious disease. However, its irrational selection and use will result the problem such as drug resistance, inappropriate dose, inappropriate frequency, inappropriate duration, adverse drug events and drug-drug interaction. Hence, health care professionals should give due attention during prescribing, dispensing and administering antibiotics for pediatric patients (7,8).
Drug therapy Problem (DTP) is an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcome. A potential DTP is not yet manifested, but if left unresolved, it may harm the patient. However, an actual DTP has results clinical manifestations like adverse drug reaction or therapy failure. DTPs may arise at all stages of the medication use process from prescription to follow up of the treatment (9,10).
Different drug therapy problem classification systems are published in literatures. To date there is no consensus and uniform methods of classification of Drug therapy problem.
However, according to Cipolle, Morley and Strand all DTPs can be categorized in to seven types including: Need additional drug therapy, unnecessary drug therapy, ineffective drug therapy, dosage too low , dosage too high, adverse drug reactions, and non-compliance (11,12).
Different factors contribute for occurrence of DTPs. These includes: missing information, poor patient's knowledge of the drug use, poly-pharmacy, administration of drugs with a narrow therapeutic range, poly-morbidity, hepatic and renal impairment (13). Pediatric group of populations are at high risk for drug therapy problems. This may be due to difference in drugs pharmacodynamics, pharmacokinetic and clinical heterogeneity such as weight, body surface area, age and organ function development which are the determinants of dose and drug selection. In addition to these, there are a limited number of studies available concerning safety and effectiveness of the drugs in this specific group of population (14).
The differences in drugs pharmacokinetics and pharmacodynamics observed in children influence the choice of the drug, dose, dosage form and dosing interval (15). The pediatric medication-use process is complex and error prone because of the multiple steps required in calculating, verifying, preparing, and administering doses (16). These factor make the pediatrics to be at high risk for drug-related problems. Therefore, all pediatric prescriptions and medication orders must be checked for its appropriateness of the dose, route and frequency with a pediatrics dosing reference (17).
Involvement of pharmacist in health care team have crucial role in preventing and resolving drug therapy problems. For instance, presence of pharmacist in the health care team and improved communication of patients with physicians, nurses and pharmacists were reduce the occurrence of medication errors in pediatric patients (18). Similarly, in 2013, Ermindo R et al (19) reported that pharmacists contributed in the therapeutic optimization and prevention of iatrogenic events in pediatric patients. Therefore, involvement of pharmacists in the care of patients with infections associated with improved clinical and economic outcomes (20).

STATEMENT OF THE PROBLEM
Infectious disease are the major causes of morbidity and mortality among children worldwide especially, in developing countries (21). Drug therapy is one of the main therapies in managing infectious disease. However; irrational use of drug therapy results serious clinical, economical and psychological problem.
Prevalence of drug therapy problems in pediatric patients varies from country to country.
The prospective cohort study conducted in China revealed that 82 DRPs were experienced by 69 patients and overall prevalence of DRPs was 21.0% (22). A total of sixty two DTPs were identified among pediatric patients in Pakistan. The most frequent DTPs were untreated conditions (25.80%), improper drug selection (19.35%) and drug interactions (9.67%) (23). Ineffective drug therapy, need additional drug therapy, drug interaction, adverse drug reaction and medication error were the common drug related problem reported in pediatric patients in different findings (24,25).
Drug therapy problem is a key factor which will affect the outcome of therapy in pediatric patients. It is a clinical problem, unless intervention done on the spot of the problems occurrence and it must be identified and resolved in a manner similar to other clinical problems. Medication errors in pediatrics are common and 5% to 27% of all pediatric medication orders result in a medication error and pharmacists must contribute to their prevention (26). It causes significant mortality and morbidity. For example, In the United States it was reported that 7000 patient were died as a result of medication errors.
Pediatric inpatients may have 3 times more medication errors than adult inpatients, and these errors are frequently harmful (27,28).
Drug therapy problem caused pediatric patients to be admitted to the hospital. For example, a prospective observational study conducted among pediatric patients in Canadian teaching hospital showed that medication-related emergency department visit was found in 8.0% of patients. Out of these 65.0% were deemed preventable (29).
Similarly study done in Brazilian hospital showed that 14.7% of the patients were admitted to pediatrics ward due to DRPs. Study done in Australia also reported that 4.3% of pediatric admissions were related to DRPs (30,31).
Drug therapy problem also causes economic crisis in health care system. For example, in 1995 in USA, cost associated to drug-related morbidity and mortality was between $30.1 billion and $136.8 billion annually. Overall, in United States the cost of drug-related morbidity and mortality exceeded $177.4 billion in 2000. Hospital admissions accounted for nearly 70% ($121.5 billion) of total costs (32,33).
Factors that contributes for occurrence of drug therapy problems in pediatric patients includes: polypharmacy, certain infectious and Parasitic diseases, type of admission, length of hospital stay and number of disease conditions (22,(34)(35)(36).
The rate of potential adverse events due to medication was higher in pediatric. For instance, a study conducted in pediatric intensive care unit (PICU) showed the the presence of pharmacists in PICU reduced the rate of serious medication errors from 29 to 6 per 1,000 patient /days (37). Similarly, It had shown that in PICU, as a result of pharmacists interventions a total of $9,135 cost per year was saved (38).
In general, prolonged hospitalizations, long-term care admissions, emergency department visits, additional physician office visits cost, morbidity ,mortality and additional prescription drugs were some of the consequences associated with DRPs (39).
Pattern of infectious disease in pediatric wards varies from country to country. Infectious diseases are the most common medical diagnosis among pediatric patients in Ethiopia (40). The magnitude of drug therapy problems and its contributing factors was not assessed among these populations in study setting as well as in Ethiopia. Consequently, this research aimed at assessing drug therapy problem and its contributing factors in pediatric patients with infectious disease admitted to Jimma university medical center.

Significance of the study
Pediatric is one of the special populations that are at high risk for DTPs since they have quite different pharmacokinetics and pharmacodynamics from that of the adult. Worldwide there are a limited number of studies available which are related to drug therapy problem in pediatric patients, particularly with infectious disease.
In the study setting there was no prior finding that identify prevalence of drug therapy problem and its contributing factors among patient with infectious disease in pediatric ward. So that the investigator believes that the finding of this study will provide a great contribution for patients, health institutions and policy makers by assessing the magnitude of drug therapy problem, identifying the type and predictors of drug therapy problem and also carrying out on spot intervention for each drug therapy problem identified. It can also be used as an input in empowering pharmaceutical care service and forwarding the significance of clinical pharmacist in pediatrics ward in the hospital.
Finally the investigator forwarded recommendations for each concerns body that helps to minimize the occurrence of drug therapy problem in the future. The result of this finding had invaluable contribution in clinical, economical and humanistic outcome for patient, parents and health institution. It will also be used as an input for further researchers.

General objective
To assess drug therapy problem and its contributing factors among patient with infectious disease admitted at pediatric ward in JUMC from April 1 to June 30, 2018 Specific objectives To assess the prevalence of drug therapy problem among patient with infectious disease admitted to pediatric ward in JUMC from April 1 to June 30, 2018 To identify type of drug therapy problem among patient with infectious disease admitted to pediatric ward in JUMC from April 1 to June 30, 2018 To identify the causes of drug therapy problem among patient with infectious disease

Study Design
A prospective observational study design was conducted over all pediatrics patients with infectious disease admitted to JUMC from April 01 to June 30 2018.

Source Population
All pediatric patients with infectious disease admitted to JUMC during study period.

Study Population
All pediatric patients with infectious disease admitted to JUMC during study period and who fulfill inclusion criteria.

Sample size and sampling technique
The sample size was calculated by using single population proportion formula based on the following assumption: Z= (1.96)2 , P =the prevalence of DTP in Zewditu hospital The size of the population is less than 10,000. Therefore; the sample size was corrected using the following correction formula.

Due to technical limitations, Equation 2 has been placed in the Supplementary Files section.
Where: n -Sample size=332 N -Number of pediatric patients with infectious disease admitted to JUMC in 2017=1623 NF=adjusted sample size So, the total sample size after 10% of non-response added = 303.6~304 patients All patients diagnosed with infectious disease admitted to pediatric ward during data collection period and who fulfilled the inclusion criteria were consecutively included in the study.

Inclusion criteria
Patients admitted to pediatric ward of JUMC with in the study period.

Age less than 18 years old
Patient diagnosed with at least one infectious disease during the study period Patients whose parents gave and signed the informed consent.

Exclusion criteria
Readmitted patients for whom data was previously collected.

Patient admitted in ICU
The hospital admission was less than 24 hours Study variables Data collection process and data quality assurance Data were collected through medical record reviews and patient interview using a prepared structured questionnaire which was translated to Afan Oromo and Amharic language for patient interview to collect information on adherence, socio-demographic, medication and disease related issues. The data collection format (Annex III) was prepared by reviewing different literatures for important variables that used to assess drug therapy problems and its contributing factors. Its content includes: patient details, diagnosis, comorbidities, duration of hospital stay, review of system and patient's investigations, intervention taken, current and past medications. The data collection involved four pharmacists (bachelor degree) and one supervisor to organize the whole activities daily.
The principal investigator reviewed all filled format so that any suggestion and corrections was given soon. Data collectors reviewed the medical chart by using prepared standard questionnaires' for all patients who fulfills inclusion criteria daily for their drug related need. Recommendations was done by a panel of experts of clinical pharmacist and forwarded to physicians and/or other health care provider during rounds.

DTPs Identification and Classification
In this study drug therapy problems were classified according to Cipolle, Morley and Strand DTPs identification and classification method. The method was refined based on

Data processing and statistical analysis
All statistical tests were performed using statistical software package, SPSS version 21.0.
Descriptive analysis was computed as frequency, mean and standard deviation (SD) for continuous variables and for categorical data. Binary logistic regression analysis was performed to examine the association between independent variables and drug therapy problem. In binary logistic regression analysis, variables with p values < 0.25 was selected for further multiple logistic regression analysis. Multiple logistic regression analyses were used to determine the independent predictors of occurrence of DTP. The Odds ratio with 95% confidence interval (CI) was calculated to measure the strength of association between predictor and outcome variables. Probability values less than 0.05 will be accepted as statistically significant. The out puts of processed data was presented using tables, graphs and figures accordingly.

Ethical consideration
Ethical clearance was obtained from ethical review committee of jimma university,institute of health. This committee wrote aletter of permission dated the 30 th February 2018; with reference number "IHRPGD/205/18" to Jimma university medical center to seek it cooperation and access the data. Pateint's infprmed consent was obtained after explaining about the purpose and procedure of the study. When the child was too young to provide informed consent,it was obtained from parents/caregivers. All the responses were kept confidential.

Operational definition and Definition of terms
Infectious disease: is a disease caused by pathogenic microorganism such as bacteria, fungi, Virus, protozoa, worms and parasites.
Adverse drug reaction: is a noxious and unintended response to a drug which occurs at doses normally used for the prophylaxis, diagnosis, or treatment of disease that occurred during the study period (42). first episode of asthma (8.19%) (Figure 2).

Medication related information of study participants
A total of 1305 drugs were prescribed for 304 patients during study period. The mean number of drug per patients was 4.29 ± 1.74. The most commonly prescribed drugs were Paracetamol 192 (63.1%) followed by Ceftriaxone 186 (61.2%) and Gentamycin 161 (53%) (Figure 3). Among study participants; 127(41.77%) of them had polypharmacy (Figure 4).

The Types and prevalence of Drug therapy Problems
From a total of 304 patients, 226 patients experienced drug related problems, with overall prevalence of 74.3%. During the study period a total of 356 DTPs were identified. From the study participants, 129 (57.1%) males' patients were exposed to drug therapy problems. The most common DTPs identified were non-compliance 102 (28.65%) followed by dose too low 98(27.53%) and in effective drug therapy 41 (11.5%) ( Figure 5).

Drugs involved in Drug therapy Problems
Different classes of drugs were involved among the patients with drug therapy problems.

The Types and status of interventions carried out
The most common type of pharmacists interventions provided were change of the medication 89 (25%) followed by adherence andcounseling79(22.19%) (Figure7). From the proposed interventions about 69.38% were fully accepted. In general the acceptance rate was 79.49 % ( Table 5).

Factors associated with drug related Problems
The result of bivariate analysis of independent variables and drug related problem showed  Table 6).

Predictors of DTPs occurrence in study populations
Multivariate logistic regression analysis was carried out to identify independent predictors of occurrence of DTPs among the study participants. Accordingly, comorbidity, Polypharmacy and prolonged hospital stay were found to be independent predictors of drug related problems among study participants. It was found that the likely hood of Therefore, presence of comorbidity, polypharmacy and prolonged hospital stay were the predictors of drug therapy problems among pediatric patients with infectious disease in this study [ Table 7].

Discussion
Study of potential drug therapy problem in pediatric patients is very essential in the prevention of complications arising from drug therapy problem (50). The prevalence and nature of all type of drug therapy problems among pediatric patients with infectious disease in pediatrics ward of JUMC had not been studied previously. Of the children included in the study, 226(74.3%) of the them had experienced at least one drug therapy problem during their hospital stayed. This showed that DTPs were common among pediatric patients with infectious disease in the study setting.
Prevalence of DTPs among pediatric patients varies from study setting to setting. In this finding the prevalence of DTPs was found to be 74.3% ,which was higher than that of the study conducted in Hong Kong (21%), Ethiopia (31.57%) and United Kingdom and the Kingdom of Saudi Arabia (45.2%) (22,34,35). This difference might be due to the difference in hospital setting, difference in drug therapy problems classification used and the availability of trained prescribers and clinical pharmacists in pediatric ward.
According to our study, being male had higher percentage of DTPs than female with the odd of 11.4%. However, the difference was statistically insignificant. Other findings also reported that DTPs were more frequent in males than in female. But, it was statistically insignificant (22,35,45). This indicated that drug therapy problems could be occurred irrespective of the sex.
The type and cause of drug therapy problems were reported in this finding. The most common drug therapy problem identified was non-compliance (28.65%) which was comparable with study done in Cote divoire (24.1%) (46). The reason may be due to majority of the patients were prescribed with multiple drugs that contributed for not to afford & difficulty in understand the instructions of drugs. Moreover, the caregiver might had less knowledge of drug use.
In the present study (27.52%) of the DTPs was found to be dose too low. This was in line with a study done in London (21.7%), Canada (19%) and Egypt (21.09%) (25,29,45). Dose too high was found to be (10.95%) in the present study which was lower than the study done in Hong Kong 19.3% (22).
This showed that inappropriate doses are more common in pediatrics which might be because of weight-based dose calculation, fractional dosing and incorrect recording of patients' weights and prescribing error (51).
ADRs are one of the major causes of iatrogenic disease, and they are as old as medicine itself. Pediatric patients may experience specific adverse effects not suffered by adults; thus pediatric patients are susceptible population to adverse drug reactions (52). Overall, incidence of patients experiencing ADR in this study was found to be 2.81% which was in line with the finding reported by Rashed et al (22) and study done in Toronto( 2.5%) (48).
The most common adverse drug reaction experienced by patients was maculopapular rash due to antibiotics such as clotrimazole and ceftriaxone. The rare adverse event such as Redman's syndrome was also reported in this finding after concomitant use of Vancomycine and ciprofloxacin. This showed that drug-drug interaction is a major factor that might cause ADR which harm patients (53).
In this study need additional drug therapy was (11.24%) which was in agreement with study done in British (9.9%) (45). In our study unnecessary drug therapy was 7.3% which was in line with study done in Addis Ababa (35). However, this finding was two times higher than study done in United Kingdom and Saudi Arabia (3.8%) (34).This indicated that duplicate drug therapy was common in study area that contributes for the patient to pay extra cost and expose them for potential ADR and drug interaction. Therefore, Prevention of duplicate drug therapy will contribute in cost saving among hospitalized patients.
The class of drugs most frequently involved in drug therapy problems was anti-infective 76.12%; which was similar with the finding reported by Rashed et al (22), Deepishka P et al (49) and Ermindo R et al (19) where systemic anti-infective were the most frequent drugs involved in DRPs. In this finding, the drugs frequently involved in DTPs were gentamicin and ampicillin. It was in contrast to study done in United Kingdom and Saudi Arabia the whereas Amoxacillin and cimetidine were the most frequent drug involved in DTPs (34). The difference might be due to these drugs were the first line drugs for infectious disease such as meningitis, pneumonia and sepsis that were prevalent in the study setting. Furthermore, these drugs were frequently prescribed than others drugs in the study setting.
The result of bivariate logistic regression analysis of independent variables and drug therapy problem showed that comorbidity, polypharmacy, number of infectious disease, type of admission, number of disease condition and length of hospital stay were associated with drug therapy problem. However, in multivariate analysis, comorbidity, length of hospital stay and polypharmacy were found to be independent predictors of drug therapy problem among pediatric patients diagnosed with infectious disease admitted to JUMC. Similarly, study done in Zewditu hospital (35), Hong Kong (22)  In the current study, presence of comorbidity was one of independent predictors for DTP.
This was also supported by the finding reported by Zed et al (29). The reason might be presence of comorbidity influence the desired outcome of other disease by increasing number of drugs, causing disease-disease interaction, drug-drug interaction, drug-disease interaction which collectively result in increased likely hood of experiencing DTPs in the study patients.
Clinical pharmacist involvement in inpatient pediatric care can significantly help to identify, resolve and prevent the drug therapy problems (48). In this finding the most common type of interventions provided was change of the medication (25%) which was similar with study done in India (50). However, it was higher than that of study done in Tirupathi (6%) (49).
This discrepancy might be due to ineffective drug therapy, which need changing of the medication, was not assessed in the finding reported from Tirupathi. Adherence and counseling (22.19%) provided for patients was higher than finding reported by Rashed et al (22). The discrepancy might be due to dosing problem was the most common type of DTP whereas non-compliance was most common DTP in this finding.
In the present study majority of intervention provided were accepted (79.49%);which was in line with study done in Toronto(81%) (48). This showed that DTPs can be prevented through effective communications and collaboration among clinical pharmacists, physicians, nurses and as well as patients (54)

LIMITATION OF THE STUDY
Since the study was conducted in single center, it may lack external validity.
The study did not classify DTPs in its severity level that means mild, moderate and severe due to the complexity of the study

CONCLUSIONS
The present finding showed that the prevalence of drug-related problems were high at pediatric ward of Jimma University medical center that needs great attention. The most frequently identified DTPs were non-compliance, followed by dose too low and ineffective drug therapy. The finding revealed that presence of comorbidity, poly-pharmacy and prolonged hospital stays were independent predictors of DTPs. From overall interventions provided, change of medications, adherence and counseling and change in drug dose were the common. The acceptance rate of recommendation by clinical pharmacist was high.

RECOMMENDATIONS
The prevalence of drug therapy problems were found to be high. Therefore, the following recommendations are forwarded based on the result of the study.

For Jimma university medical center
Clinical pharmacists have be recruited and assigned to pediatric ward of Jimma university medical center in order to provide better pharmaceutical care services.
The hospital have to establish the forum that encourage physicians , nurses and pharmacist relationship for better pharmaceutical services

For patients/caregiver
Take/give his/her medicine as prescribed if you have forgeton the instructions how to provide the drugs, ask pharmacist or health professional before providing for the patients

For federal ministry of health /policy maker
Have to strengthen the reporting and monitoring mechanism of drug therapy problem

For researchers
Conduct a research on clinical, economical and humanistic impact of drug therapy problem among pediatric patients with infectious disease admitted to the study area.

Declarations
The dataset supporting the conclusions of this manuscript is included within the article.       Figure 1 The top ten infectious diseases diagnosed among patients admitted to pediatric ward of JUMC from April 1 to June 30, 2018.

Figure 2
The top ten comorbidities diagnosed among patient with infectious disease at pediatrics ward of JUMC from April 1 to June 30, 2018    Type of intervention provided for patients diagnosed with infectious disease admitted to pediatric of JUMC from April 1 to June 30, 2018