Evaluation of antibiotic prescriptions and use in under-five children in Ibadan, SouthWestern Nigeria

Background Irrational antibiotic prescriptions for children is a global concern requiring periodic evaluation and monitoring. Objectives To assess appropriateness of antibiotic prescribing for under-five children, as well as evaluating mothers' usage of antibiotics for their under-five and reason(s) for use. Method Cross-sectional review of out-patient case-notes of under-five using principles of antibiotic prescribing and a questionnaire-guided interaction with under-five mothers. Results Nearly all (445;98.9%) antibiotic prescriptions were based on signs and symptoms indicative of bacterial infection. Only 3(0.7%) had the initial antibiotic regimen modified. Nine (2.0%) had documented evidence of sensitivity test requested before antibiotic prescribing. Presence of infection or need for antibiotic therapy was established in 190(42.2%). Majority (324;72.0%) of mothers had administered antibiotics to their under-five. Of these, 157(48.5%) were prescribed by physicians and 79(24.4%) were self-recommended. Educational status of mothers significantly influenced antibiotic usage. Conclusion Antibiotic prescriptions for under-fives was largely based on symptoms indicative of bacterial infections, thereby corroborating the widespread empirical antibiotic prescribing. Considerable number of mothers engaged in self-recommendation of antibiotics for their under-fives. Thus, there is a need for continuous enlightenment of prescribers and mothers on rational use of antibiotics, while microbiological confirmation of clinical diagnosis is encouraged for evidence-based antibiotic prescribing.


Introduction
Antibiotic prescriptions for children is a cause for concern in both developed and developing countries, especially for its excessive use in non-established infections or in infections with viral etiology [1][2][3][4] . In Nigeria, children below the age of 14 years constituted more than 40% of the population 5,6 , while children aged five years and below constitute the bulk of patients attending the paediatric out-patient clinics 7 . These age groups are particularly vulnerable to many communicable and infectious diseases, with mortality among them usually very high 6,7 . The United Nation Children Endowment Fund (UNICEF) reported in 2013 that about 2300 under-five children in Nigeria die every day 8 .
Although antibiotics play a crucial role in reducing child morbidity and mortality 9 , its irrational use directly increases antibiotic resistance by promoting the emergence of resistant bacteria leading to increased rates of treatment failures and more severe illness episodes with higher costs and mortality rates [10][11][12][13] . Hence, the need for special atten-cost with the right information. Thus, rational antibiotic prescription has to be tailor-made for individual patient taking into account the diagnosis, age, sex, weight, microorganism susceptibility, vital organ functions, drug and food interactions, as well as socioeconomic background of patient 14,15 .
In many low-and medium-income countries, indiscriminate and excessive use of antibiotics without medical guidance is largely facilitated by inadequate regulation of distribution and sale of prescription drugs 16,17 . Studies have documented that a large number of mothers/ caregivers do not consult the physician when their children/wards fall sick, instead they either visit the nearby pharmacies or patent medicine vendors to make complaints and medicine will be recommended [18][19][20] . Some of them also considered self-medication of antibiotics for their wards/children, or consult a neighbour who may be having some left-over drugs 21 from previous use. Such irrational use of antibiotics causes avoidable drug-related adverse effects 22,23 as well as contributes to antibiotic resistance 24,25 and unnecessary medical costs. In addition, a number of physician-related factors contributing to inappropriate or irrational prescribing has been identified to include workloads and time pressure, inadequate drug knowledge and experience, diagnostic uncertainty, incomplete patient information, prescriber's perceived demand and expectation, as well as consideration about susceptibility among others [26][27][28][29][30][31] . Therefore, there is a need for continuous medical education and training for prescribers on rational antibiotic prescribing, as well as enlightenment of the general public on proper use of antibiotics in order to reduce the menace of antibiotic resistance. Among the numerous interventions proposed by the World Health Organization to tackle irrational antibiotic prescribing is the necessity for prescribers to adopt and use protocols or guidelines based on strong evidence for the use of antibiotics 32 . Adopting these guidelines will standardize treatments, minimize dosage mistakes, avoid individual decisions, as well as ensure prioritization of decision based on clinical evidence 33 .
Studies have been carried out to evaluate antibiotic use in public health facilities especially among adults [34][35][36][37][38] , and many of these studies suggest the need for periodic audits of antibiotic prescriptions and use with a view to ensure sustained interventions to minimize negative consequences arising from inappropriate use of antibi-otics. In Nigeria and many other developing countries, research assessing appropriateness of antibiotic prescriptions and usage in accordance with principles of antibiotic prescribing is scarce. This study therefore aimed at evaluating appropriateness of antibiotic prescriptions for under-five children in selected secondary and tertiary healthcare facilities in Ibadan, Oyo state, SouthWestern Nigeria, using antibiotic prescribing evaluation criteria developed by Adorka et al 39 . Profile of antibiotics used by mothers for their under-five children and reasons for use were explored, while relationship between mother's educational status and some specific response on antibiotics used was subsequently investigated.

Study site
This study was carried out in three healthcare facilities in Ibadan Metropolis namely Adeoyo Maternity Teaching Hospital, Yemetu; Oni and Son Children Hospital, Ring Road; and the University Health Service (UHS), Jaja, University of Ibadan, Ibadan, all in Oyo state, SouthWestern Nigeria. Adeoyo Maternity Teaching Hospital is a tertiary facility that caters for the healthcare needs of several categories of ambulatory and institutionalised patients, and it is a well-known hospital for maternity services and children care. Oni and Son Children Hospital is majorly for children-related treatment and care. The University Health Service is a secondary healthcare facility which provides medical services for students and members of the university community, and it is one of the major routine immunisation centres in Ibadan Metropolis.

Study design
A cross-sectional retrospective review of out-patient case notes of under-five children in selected hospitals between July and December, 2015 using principles of antibiotic prescribing adapted from Adorka et al 39 . A questionnaire-guided prospective interaction with mothers of under-five children who attended the immunisation clinic of selected hospitals was subsequently carried-out for four consecutive weeks. Ethical approval was obtained from the University of Ibadan/University College Hospital Institution Review Board with the approval number NHREC/05/01/2008a

Study population
Out-patient case notes of under-five children in the medical record unit of Adeoyo Maternity Teaching Hospital and Oni and Son Children Hospital, as well as mothers of under-five children who visited Adeoyo Maternity Teaching Hospital and UHS for routine immunisation of their children within the period of study.

Sample size determination
Based on estimated record of a total of 22,200 out-patient case notes for under-five children from Oni and Son Children Hospital and Adeoyo Maternity Teaching Hospitals between July and December, 2015, a representative target sample size of 450 case notes was determined using Yamane (1967) sample size formula 40 . Also, a total of 3700 under-five children who were regularly been treated in Adeoyo Maternity Teaching Hospital and UHS on a monthly basis was obtained from the medical record unit of the hospitals. Based on the estimated population and allowing for attrition rate, a target sample size of 450 was also calculated to guide enrollment of under-five mothers for the prospective interaction.

Inclusion criteria/Exclusion criteria
The most recent prescription contact in selected case notes of under-five children, containing at least one antibiotic was included for review. Prescriptions with no antibiotics and those with incomplete information such as patient's age were excluded. Also, mothers/caregivers who brought their under-five children to the hospitals for routine immunisation, and who consented to participate in the study were enrolled. Mothers of children older than five years and those who declined participation were excluded.

Sampling and recruitment procedures
All the under-five out-patient case notes that met the inclusion criteria from selected hospitals within the study period were chronologically arranged, with every other case note subsequently selected for review. For the prospective phase, mothers of under-five children were approached for participation in the study while waiting for their children's turn of routine immunisation schedule. Details of objectives and procedure of the study were explained to individual participant, after which voluntary informed consent was obtained from every participant to signify their intention for participation. Confidentiality of responses and anonymity were assured, while they were informed that participation is voluntary. Only consented mothers of under-five children were consecutively enrolled and administered the questionnaire.

Instrument for data collection
The retrospective review of case notes was guided by Adorka et al 39 antibiotic evaluation criteria based on principles of antibiotic prescribing. The evaluation tool was designed with a 'Yes' or 'No' response option, and was largely based on (a) principles of establishing the presence of bacterial infections before administration of antibiotics 41-43 (b) principles of establishing potential sources of infections or co-morbid conditions predisposing patients to certain infections prior to prescribing antibiotics for prophylactic purposes 43 and (c) principles of making appropriate antibiotic selection for empiric or definitive treatment of infections including the need for and ensuring the effectiveness of prescribed antibiotics 4142, 44 . Prospective interaction with mothers of under-five children was guided by pre-tested and validated structured questionnaire comprising three sections: Section A gathered socio-demographic data of mothers of under-five children including age, educational status and occupation. Section B assessed opinion of mothers on antibiotics used for their under-five children at one time or the other. Section C evaluated data on mothers' perceived effectiveness of antibiotics used for their under-five children among other questions.

Pre-test and validation of instrument
The instruments were assessed for content validity by two academic scholars in the department of Clinical Pharmacy and Pharmacy Administration, University of Ibadan. Face validity was done among five mothers of under-five children from Oni and Son Children Hospital to ascertain appropriateness of sampling procedure vis-a-vis the study design. Ten case notes from the UHS were used to pre-test the antibiotic prescribing evaluation criteria. Necessary modifications were made thereafter to ensure clarity and comprehension of the questions before the final version of the questionnaire was administered to participants.

Data analysis and management
Data obtained were sorted, coded and entered into Predictive Analytic Software (PASW) Version 20.0 for data analysis and management. Descriptive statistics including frequency and percentages was used to summarise data. Chi-square test was used to evaluate the relationship between educational status of mothers/caregivers and some specific response on antibiotics used for their under-five at p < 0.05 considered significant.

Results
There were 243 (54.0%) case notes reviewed from Oni and Son Children Hospital and 207 (46.0%) from Adeoyo Maternity Teaching Hospital. The mean age of under-five children whose case notes were reviewed was 17.5 ± 15.6 months. Majority, 431 (95.8%) had age ≤ 24 months, 14 (3.0%) were within the ages of > 24 -≤ 48 months, and 5 (1.1%) were in the age range of > 48 -≤ 60 months. Out of a total of 1742 medicines reviewed from 450 prescription contacts, 521 (29.9%) were antibiotics. Almost all, 445 (98.9%) prescriptions had the anti-biotics prescribed based on signs and symptoms indicative of bacterial infections. A substantial proportion, 445 (98.9%) of antibiotics prescribed were broad-spectrum agents for all possible pathogens associated with the site of infection. Only 3 (0.7%) prescriptions had the initial antibiotic regimen modified by addition of other antibiotics. Nine (2.0%) had documented evidence of culture and sensitivity test results requested before initiation of antibiotic therapy. Details of retrospective assessment of under-five antibiotic prescriptions using individual criteria are shown in Table 1. The criteria combination for prescription assessment showed that 190 (42.2%) antibiotic prescriptions were established based on the presence of infection or the need for antibiotic use. A total of 185 (41.1%) antibiotic prescriptions were based on the presence of suspected bacterial infection, without evidence of laboratory test confirmation (Table 2).  Category definition for appropriateness of antibiotic prescribing showed that almost all the antibiotic prescrip-tions (438; 97.3%) were empirically prescribed for the treatment of infection without adherence to the principles of antibiotic prescribing (Table 3). Antibiotics empirically prescribed without adherence to principles of antibiotic prescribing and in conditions for which antibiotics were not  Table 4.  (Table 5).   ) is used as a guide to ascertain dosage regimen appropriateness. Self-medication is considered as antibiotic usage without prescription from a physician. Appropriate source of antibiotics information is considered as information received from the primary care physician.

Discussion
Although antibiotics play a crucial role in reducing child morbidity and mortality 9,10 , their inappropriate use may directly increase antibiotic resistance by promoting the emergence of resistance strain of bacteria 10,11 . World Health Organisation has stated that antimicrobial resistance is one of the world's most serious public health problem and is largely caused by inappropriate prescribing and use 32,45 . Thus, periodic evaluation and monitoring of antibiotic use especially in vulnerable population such as under-five children is essential. From the present study, nearly all the antibiotics prescribed (98.9%) were based on signs and symptoms indicative of bacterial infections, and > 98% were broad-spectrum agents for all possible pathogens associated with the site of infection. This largely indicates that most of the antibiotics prescribed for the under-five children were empirically prescribed, thereby further corroborating the widespread empirical nature of antibiotic prescribing in many developed and developing countries 36,[46][47][48][49] .
In contrast, the principles of antibiotic prescribing emphasize the need for evidence-based prescribing of antibiotics based on laboratory confirmation of implicated organism(s) before the initiation of antibiotic regimen 41,43 . However, in this study, the microbial, culture and sensitivity, a gold standard test for confirmation of bacterial infection was requested before initiation of antibiotic therapy in only few cases (2.0%). Although, microbiological diagnosis is important for obtaining accurate diagnosis of bacterial infection, its utility in routine clinical practice is limited by a number of factors 41,50 including time constraints or delay in obtaining laboratory results -usually 24 -72 hours in most cases, expertise required for appropriate specimen collection and processing, as well as costs of laboratory investigations among others. Thus, the clinical manifestations presented by a patient may help in making decision for empirical antibiotic therapy especially for acute infections in under-five children where prompt clinical diagnosis and treatment are desired to avert fatal consequence(s) 46,48,51 . In such situation, the initial antibiotic selection for empirical therapy should rely on broad-spectrum agents until culture and sensitivity data are available to determine the implicated organism(s). Once there is a laboratory evidence confirming the susceptible organism(s), a prompt switch to a cost-effective antibiotics with the narrowest possible spectrum of activity is desirable for continuation of therapy 46,48,51 . In general, appropriate use of antimicrobial agents involve obtaining an accurate diagnosis to determine the need for and timing of antimicrobial therapy, understanding how dosing affects the antimicrobial activities of different agents, tailoring treatment to host characteristics using narrow-spectrum agents and shortest duration of therapy 41,50 . Therefore, there is a need for continuous medical education and training for prescribers on rational antibiotic prescribing, while ensuring improved access to microbiological-based laboratory facilities. This will guarantee better therapeutic outcomes with reduced incidence of antibiotic resistance.
Cephalosporins, most especially cefuroxime were the commonly prescribed antibiotics for under-five in the facilities studied. This is followed by penicillins, specifically amoxicillin-clavulanic acid. Previous studies have also reported cephalosporins and penicillins as the most commonly prescribed antibiotics for treatment of different infections in under-five children 6,9,52 . Cephalosporins are broad-spectrum bactericidal agents that have similar mechanism of action with penicillins, but are less susceptible to beta-lactamases 53,54 . Although, many of the antibiotics used by mothers/caregivers for under-five children at one time or the other were prescribed by physician, a substantial number of mothers also self-recommended the administered antibiotics for different kinds of symptom suggestive of infections. Many of the mothers/caregivers claimed to administer the antibiotics largely because of previous experience of effectiveness of use to their older children. Nevertheless, self-medication with antibiotics for prevention of future illness or active treatment of infections should be largely discouraged. Antibiotics should only be used when prescribed by a physician and this must be evidence-based in line with the principles of antibiotic prescribing [41][42][43] . Hence, the need for education and consistent enlightenment of mothers/caregivers on appropriate use of antibiotics for their under-five children. Rational use of antibiotics will help to stem the tides of continual antibiotic resistance since there are limited range of antibiotics available for the treatment of most infections 41,55 . The practice of self-medication with antibiotics by mothers of under-five may perhaps be linked to unregulated distribution of prescription drugs in many low-and middle income countries 14,15,[56][57][58] including Ni-geria. In many resource-poor countries, prescription-only medicine and over-the-counter drugs can be purchased in most pharmacies and patent medicine stores without prescription 14,15,[56][57][58] . However, continued exposure of individual to antibacterial or antimicrobial agents is a major precursor to antibiotic resistance by promoting emergence of resistance bacteria strain [58][59][60] .
Interestingly, educational background of mothers significantly influenced decision for antibiotic usage for the under-five children. Higher level of education significantly impacted on mothers' choice of appropriate antibiotics for suspected symptoms of infections, as well as favors mothers' tendency to engage in antibiotic self-medication practices. This is consistent with previous studies 16,18 which reported education of mothers as an influential factor on knowledge of use of antibiotics in cases of upper respiratory tract infections. Mothers/caregivers who are better educated are more likely to understand basic information on health education, as well as be able to recognise basic signs and symptoms of common childhood infections. Prescribers therefore need to intensify efforts at ensuring proper clarification of antibiotics information for mothers/caregivers of under-five, especially those with no formal education or those who possess minimal level of literacy. Furthermore, education on measures to properly handle left-over antibiotics by mothers should be appropriately reinforced during patient provider encounters. This becomes necessary on account of the fact that substantial proportion of mothers in this study mentioned methods for handling unfinished antibiotics to include discard/throw away the remaining antibiotics, as well as keeping the antibiotics for future use. These irrational disposal methods for unused antibiotics should be essentially discouraged, while mothers should be educated and enlightened on the need to always ensure completion of the recommended course of antibiotic regimen.
Despite the useful information from the present study, its limitations include the likelihood of memory or recall bias among mothers/caregivers with respect to use and dosage regimen of antibiotics administered to their under-five children. Also, opinions of under-five mothers who participated in this study may not be entirely representative of all mothers in the country, although, the proportion of participants who were engaged in this study is largely a representative sample size for the study sites.
Another limitation of this study is the fact that only the case notes of ambulatory under-five children were reviewed, while specific disease condition(s) or illness of under-five for which an antibiotics was prescribed was not distinctly explored. Future study may therefore need to take these gaps into consideration in order to ensure a far reaching conclusions on the appropriateness of antibiotic prescribing practice. Nevertheless, the strength of the present study may be linked to ability of the evaluation criteria to allow for a detailed description and assessment of antibiotic prescribing trends based on principles of antibiotic prescribing. Many of the previous studies 34-38 that evaluate drug use in public health facilities focus largely on prescription reviews using World Health Organization prescribing indicators which does not include detailed account of antibiotic prescribing trends.

Conclusion
Antibiotic prescriptions for under-five children in the facilities studied was largely based on signs and symptoms indicative of bacterial infections, thereby further corroborating the widespread empirical antibiotic prescribing. Cephalosporins and penicillins classes of antibiotics were mostly prescribed for treatment of infections in the under-five, with considerable number of mothers who had engaged in self-recommendation of antibiotics at one time or the other. Thus, there is a need for consistent enlightenment of mothers on proper use of antibiotics. Also, continuing medical education and training for prescribers on rational antibiotic prescribing should be reinforced, while microbiological confirmation of clinical diagnosis is encouraged to ensure evidence-based antibiotic prescribing.