Patrick O Erah,, MPharm, PhD 1,2* and Mary O Ehiagwina,, PharmD 2. 1 Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, Nigeria. 2 Department of Clinical Pharmacy &, Faculty of Pharmacy, University of Benin, Benin City, Nigeria. *Corresponding author: Email: p_erah@yahoo.com Abstract This study was undertaken to evaluate rational prescribing and cost of antibiotics in four referral healthcare facilities in Edo State. In a retrospective cross-sectional study, prescriptions of 800 systematically selected inpatients who received antibiotics therapy were evaluated. Prescribing indicators, DDDs and local costs of the antibiotics expressed in a ratio of the international prices as median price ratio (MPR) were evaluated. Number of antibiotics per encounter, percentages prescribed by generic name and encounter with injection, proportions of antibiotics essential drugs list and those used for prophylaxis were 1.81±0.01, 45.31±8.70%, 77.07±3.34%, 92.75±1.77% and 47.25±0.35%, respectively. Either relatively too low or high doses were used in most cases. MPR varied from 0.15 to 14.32 with 87.5% of the antibiotics having prices much higher than the international prices. It is concluded that inappropriate use of antibiotics still exists in the health facilities and most antibiotics cost several times more than the international prices. Keywords Antibiotics rational prescribing, Relative cost of antibiotics, Median price ratio (MPR), Daily Defined Doses (DDDs) and Southern Nigeria. Key Points 1
Inappropriate, ineffective and inefficient use of medicines in health facilities occur worldwide and have been reported in several health facilities in Nigeria. Irrational use of antibiotics increases the risks of bacterial resistance and therapeutic failures of antibiotics To improve prescribing habits, several educational programmes including seminar and workshops for pharmacists and medical doctors have been successfully organized, and changes in the curricula of both medical and pharmacy students have taken place across the country. This study has revealed that irrational prescribing still exists in the four referral hospitals studied in Edo State For most antibiotics, patients pay several times more than the internationally accepted prices. Introduction Over the last decades, Nigeria has always had limited budget allocated to health care especially for drug procurement. The pharmaceutical policy in the country is based on the concept of essential medicines and procurement of generic medicines. Like many other countries (developing and developed), inappropriate, ineffective and inefficient use of medicines have been reported to occur in many health facilities 1-3. Common types of irrational use of medicines include non-compliance with health worker prescription, self-medication with prescription drugs, overuse and misuse of antibiotics, overuse of injections and relatively safe medicines, use of unnecessary expensive medicines and poor patient compliance 1-4. Many individuals or factors influence the irrational use of medicines such as patients, prescribers, the workplace environment, the supply system including industry influences, government regulation, and drug information and misinformation 3,4. For prescriber, promotional activities of pharmaceutical companies, training 2 received by the prescriber, and problems experienced with particular classes of medicines are some contributing factors which influence the decision to prescribe any particular medicine and the doses used. In a study in Kentucky, 60% of patients were prescribed antibiotics for common cold 5. A similar surveillance on dosages, duration and routes of administration of antimicrobial agents showed that over 70% of patients were prescribed inadequate dosages of these agents 6. Irrational use of antibiotics is an important cause of bacterial resistance and may even lead to infections that are worse than the originally diagnosed one 7,8. As antibiotics can account for 25-65% of all prescribed medications 9 and 10-15% of total health care cost in the developed societies, while it may be up to 30-40% in some developing countries, rational use of antibiotics that will improve quality, increase accessibility and equity of health and medical care for the community is of the essence. Over the last decade, efforts to improve rational use of medications have been intensified worldwide.
HEALTH CARE FACILITIES IN SOUTHERN NIGERIA In 2003, the irrational use of medicines, including antibiotics, in some health facilities in both Edo and Delta States in Nigeria was reported 3. Since then several educational programmes including seminars and workshops for pharmacists and medical doctors have been successfully organized, and changes in the curricula of both medical and pharmacy students have taken place across the country in an effort to impact adequate knowledge and skills on rational use of medications on both medical and pharmacy professionals. However, increasing resistance of many antibiotics to common bacterial infections is being reported 10. The monitoring of medications use and knowledge of prescription habits are some of the strategies recommended for curtailing and controlling medication cost and its effect on national budget 11. Medications utilization monitoring also provides further input into the correlation of utilization with medication effectiveness, prescribing habits, and time dependencies 12. Therefore, this study was undertaken to specifically evaluate rational prescribing of antibiotics in four tertiary health care facilities in Edo State and the costs of the antibiotics relative to the internationally accepted prices. Specifically, we evaluated rational prescribing of the antibiotics in the health facilities using relevant World Health Organisation (WHO) prescribing indicators, related the doses used to the internationally defined daily doses (DDDs) and compared the local prices of the antibiotics with internationally accepted prices. Methods The study was carried out in four referral government hospitals in Edo State in the southern part of Nigeria. These hospitals are University of Benin 3 Teaching Hospital, Benin City (UBTH), Central Hospital Benin City (CHB), Central Hospital, Auchi (CHA) and Central Hospital, Uromi (CHU). While UBTH is a 650-bed federal government funded tertiary hospital, CHB is 450-bed, and CHA and CHU are 150-bed Edo State Government funded hospitals. These referral hospitals serve a population of over 2.5 million people in the State, with an average monthly in-patients population of over 500 2,000 per month, depending on the hospital. In a retrospective cross-sectional study, the medical records of 800 patients admitted in the health facilities from January to December 2008 were evaluated. Included in the study sample were case notes of patients above 19 years who received at least one antibiotic prescription at not more than one recorded admissions in each hospital. For the purpose of this study and the usual practice in Nigeria, a prescription was considered as all medicines recommended for a patient by the attending physician per encounter. The case notes of these patients were systematically selected as previously described 13. Case notes of all out-patients and patients below 19 years were excluded from this study. Equal numbers of prescriptions were randomly selected from the case notes in each facility on quarterly basis in the year, to minimize bias that may arise from seasonal changes which can often lead to variation in the disease patterns. For data collection, a database was created in Epi-Info (CDC, USA/WHO, Geneva). The data collected from each patient s case notes and entered directly into the database included gender, age, diagnosis, admission period, number of antibiotics prescribed, total number of medicines prescribed,
HEALTH CARE FACILITIES IN SOUTHERN NIGERIA result of culture and sensitivity testing, antibiotic medication information (name, dosage form, generic or brand, route, dose and frequency, condition for prescription and cost of the antibiotics) and outcomes of therapy. Outcomes of therapy was determined in terms of cured, died, referred, and discharged on request or against medical advice. The WHO prescribing drug use indicators namely, average number of medications per admission, percentage of medications prescribed by generic name, percentage of encounters with antibiotics injection prescribed, and proportion of antibiotics prescribed from the hospital formulary were determined 13. Other indicators evaluated were proportion of antibiotics used for prophylaxis, proportion of antibiotics used for diagnosed infections, average admission days, cost of antibiotics, number of positive biological specimen cultures and sensitivity tests for which antibiotics were administered. The local prices of antibiotics were based on the respective hospital s pharmacy prices. Appropriate approval for this study was sought and received from the hospital authorities prior to the study. Relevant guidelines for maintaining the confidentiality of information were strictly followed. Data Analysis Computations on drug usage pattern were carried out as earlier described 13. The identification of all antibiotics that have defined daily doses (DDDs) assigned by the WHO Collaborating Centre for Drug Statistics Methodology (Guidelines for ATC classification and DDD assignment) was carried out and the appropriateness of doses of the antibiotics administered was evaluated in relation to the 4 calculated DDDs of the respective antibiotics 14. Local prices of the antibiotics (based on the local pharmacy prices) were expressed as a ratio of the international prices to obtain the median price ratio (MPR) as previously described 15. For this purpose, the local prices were expressed in US dollars and divided by the respective international reference prices in US dollars. An MPR ratio of 1 means that the local price is equivalent to the reference price. The international reference prices were taken from the 2008 Management of Sciences for Health (MSH) International Drug Price Indicator Guide available at http://erc.msh.org or the British National Formulary 2008 edition available at http://www.bnf.org for products not available in MSH database. Descriptive statistics (mean, SD, range) were calculated as appropriate and reported. Proportional data were analyzed using Chi-square test or Fisher s Exact test. At 95% confidence interval, 2-tailed p values less than 0.05 were considered to be significant. Results The age and sex distribution of patients involved in this study are given in the Table 1. Patients involved were between 22 and 78 years of age. No significant difference was observed between the proportion of males and females.
HEALTH CARE FACILITIES IN SOUTHERN NIGERIA Table 1: Age and sex distribution of selected patients treated in 4 tertiary health care facilities in Edo State Age (yrs) Male (%) Female (%) 20-24 44 (5.5) 30 (3.8) 25-34 77 (9.6) 75 (9.4) 35-44 70 (8.8) 82 (10.3) 45-54 69 (8.6) 58 (7.3) 55-64 94 (11.8) 84 (10.5) >65 57 (7.1) 60 (7.5) Total 411 (51.4) 389 (48.6) The indicators for antibiotic prescription in the health facilities are provided in Table 2. Other than the prescription of medicines as injections and in generic names, there was no significant difference between the data for males as compared to females in the indicators. Evaluation of the total number of antibiotics prescribed as a ratio of the total number of medicines revealed that every 100 medicines prescribed had approximately 28 antibiotics with each patient receiving about 2 antibiotics (1.81±0.01) per encounter. Generic prescribing was low (45.31±8.70%) but the use of injections was high (77.07±3.34%). Over 91% of the antibiotics prescribed were in the essential drugs list. A high proportion of the antibiotics (47.25±0.35%) were prescribed for prophylaxis. Each patient spent an average of 7 days on admission and an average US$9.05±6.89 for the antibiotics. Even though culture and sensitivity of biological samples for 416 (52%) of the patients were requested, only the report of 4 sensitivity tests were found on record. The conditions for which antibiotics were prescribed included trauma (14.3%), malaria fever (14.1%), cardiovascular diseases (13.5%), retroviral disease (11.8%), metabolic disorders (3.4%), gastroenteritis (2.9%), intestinal obstruction (4.4%), enteric fever (3.1%), respiratory tract infection (5.4%), central nervous system disorders (6.1%), peptic ulcer disease (3.0%), reproductive tract infection (1.8%), anaemia (1.6%), urinary tract infection (1.4%), liver disease (2.1%), renal disorders (1.4%), sepsis (1.1%), pancreatitis (2.1%), burns (1.5%), wound infection (1.4%), and osteoarthritis (0.8%). 5
Table 2: Indicators for antibiotic prescription in four selected health facilities in Edo State Indicators Male Female Mean±sd P - value WHO Prescribing indicators Average number of antibiotics per encounter Average number of medicines per encounter Percentage of antibiotics prescribed by generic name Percentage of encounter with an injection prescribed Proportion of antibiotics prescribed from the essential drugs list Other indicators Proportion of antibiotics used for prophylaxis 1.81±0.73 1.80±0.75 1.81±0.01 2.79±2.02 2.83±2.39 2.81±0.03 51.46 39.15 45.31±8.70% < 0.01 79.43 74.71 77.07±3.34% 0.04 91.5% 94% 92.75±1.77% 47.50% 47% 47.25±0.35% Average admission days (range) 6.7±5.69 (1-28) 7.57±7.18 (1-66) 7.13±6.44 Average cost of antibiotics prescribed per patient Culture and sensitivity tests (%) No. of positive biological specimen cultures and sensitivity test N1,095.73±708.0 (US$7.13±5.90) N1,085.04±939.10 (US$9.04±7.83) 218 (27.3) 198 (24.8) Blood cultures 202 (25.3) 170 (21.3) Urine cultures 12 (1.5) 16 (2.0) Others 4 (0.5) 12 (1.5) N1086.53±826.93 (US$9.05±6.89) 6
Figure 1 shows the distribution of the number of antibiotics per prescription sheet. More patients (40.4%) were prescribed 2 antibiotics than 1, 3, 4 or 5 antibiotics per encounter. The outcomes of the antibiotics prescribed are shown in figure 2. As many as 16.12% of the patients died while majority (39.25%) recovered from the cause of their illnesses and others were either discharged on request or against medical advice. The distribution of the calculated and international DDDs are provided in Table 3. Of the 16 antibiotics whose international DDDs were obtained, the calculated DDDs for benzylpenicillin, cefuroxime, cotrimoxazole, flucloxacillin and metronidazole were lower than the international DDDs; it was even 3 times lower in the case of ceftazidime. However, the calculated DDDs were higher for amoxicillin and amoxicillin-clavulanic acid combination, clarithromycin, doxycycline and erythromycin than the international DDDs. 250 200 Number of patients 150 100 50 Male Female 0 1 2 3 4 5 Number of antibiotics prescribed Figure 1: Distribution of antibiotics prescribed 7
No of patients 180 160 140 120 100 80 60 40 20 0 Male Female Cured DR DAMA Died Referred Outcomes of therapy Figure 2: Distribution of outcomes of patients who received antibiotics (DR, discharged on request; DAMA, discharged against medical advice) Table 4 shows the local prices and international prices per unit of antibiotics. The MPR for the antibiotics varied from 0.15 to 14.32. Of the 24 antibiotics with international prices, only clindamycin, cotrimoxazole and benzylpenicillin. were much lower in their prices than the international prices. For as much as 87.5% of the antibiotics, the patients who received them paid more than the international prices, with some medicines being over 14 times the international prices. 8
Table 3: Defined daily doses (DDD) of antibiotics utilized in four selected health facilities in Edo State Name of drug Strength Calculated DDD (mg) International DDD (mg) Amoxicillin 500 mg 1500 1000 500 Amoxicillin + clavulanic acid 625 mg 1350 1000 350 Ampicillin + cloxacillin 500 mg 2000 2000 0 Deviation* Benzylpenicilln 600 mg/vial 2400 3600-1200 Ceftazidime 2000 mg 2000 6000-4000 Ceftriaxone 1000 mg/vial 2000 2000 0 Cefuroxime 250 mg 1000 2000-1000 Ciprofloxacin 500 mg 1000 1000 0 Clarithromycin 500 mg 1000 500 500 Cotrimoxazole 480 mg 1920 1920 0 Doxycycline 100 mg 200 100 100 Erythromycin 250 mg 1500 1000 500 Flucloxacillin 250 mg 1000 2000-1000 Gentamicin 40 mg/ml 240 240 0 Metronidazole 400 mg 1200 1500-300 Ofloxacin 200 mg 400 400 0 *Deviation of calculated DDD values from the international DDD values 9
ANTIBIOTICS FOR IN-PATIENTS TREATED IN SELECTED TERTIARY Table 4: Local versus international price comparison of antibiotics utilized in four tertiary health facilities in southern Nigeria Name of drug Strength International Price (US$) Local Price per unit (US$) 1 MPR 1 Ciprofloxacin O 500 mg 0.0298 0.4237 14.32 Ofloxacin O 200 mg 0.0349 0.4237 12.14 Ceftriaxone P 1000 mg/vial 0.8821 5.9322 6.73 Ceftazidime P 1000 mg/vial 2.435 13.5593 5.57 Metronidazole O 400 mg 0.0066 0.0339 5.14 Cephalexin O 500 mg 0.085 0.4237 4.99 Flucloxacillin O 250 mg 0.0720 0.3390 4.71 Clarithromycin O 500 mg 0.2731 1.2712 4.65 Doxycycline O 100 mg 0.0174 0.0678 3.90 Amoxicillin+Clavulanic acid O 625 mg 0.2896 1.0169 3.51 Cefuroxime P 750 mg/vial 1.3376 4.6610 3.48 Tetracycline O 250 mg 0.0081 0.0254 3.14 Ampicillin+sulbactam P 1500 mg 2.3115 6.3559 2.75 Gentamicin P 40 mg/ml 0.0728 0.1695 2.33 Cefuroxime O 250 mg 0.5908 1.2712 2.15 Amoxicillin+Clavulanic acid P 1200 mg/vial 3.5532 7.6271 2.15 Ciprofloxacin P 2 mg/ml 0.0062 0.0127 1.93 Ampicillin+cloxacillin O 500 mg 0.0459 0.0678 1.48 Amoxicillin O 500 mg 0.0468 0.0678 1.45 Erythromycin O 250 mg 0.0911 0.1271 1.40 Metronidazole P 5 mg/ml 0.35 0.4237 1.21 Clindamycin O 300 mg 0.2 0.0593 0.30 Cotrimoxazole O 480 mg 0.145 0.0593 0.20 Benzylpenicillin P 600 mg/vial 0.42 0.1271 0.15 US$1.00 = N118.00; MPR = median price ratio; O = Oral; P = Parenteral Practice 10 Pharmacy
ANTIBIOTICS FOR IN-PATIENTS TREATED IN SELECTED TERTIARY 1 p<0.001 Discussion All infections are potential threats to life and antibiotics are life-saving instruments that are largely responsible for improved quality of life and increased life expectancy in many countries when they are used appropriately. However, the common occurrence of ineffective and inefficient use of these agents at health facilities in developing and developed countries is not new 1,2. The continuous monitoring of the utilization of antibiotics is important in implementing approaches that can be effective in controlling their inappropriate use. For example, a study at health facilities in Indonesia showed that the monitoring was effective in reducing injection use, antibiotic use and average number of drugs per prescription 16. Although progress has been made in some aspects of rational prescribing by the prescribers in this study, inappropriate prescribing of antibiotics still exist in the settings studied thus pointing to the fact that the educational interventions for physicians and medical students over the years in Nigeria appear not to have achieved the desired goal as far as antibiotic therapy is concerned. Prophylactic use was high as approximately 1 in every 2 patients received prophylactic antibiotics prescription while on admission (Table 2). The reason often given by the physicians for prescribing antibiotics for prophylaxis is to cover the possibility of a missed diagnosis of significant bacterial infection. The Practice 11 high prophylactic antibiotic use was compounded by poor documentation of culture and sensitivity tests. Over-use of injections was unjustifiable from the evidence in the patients case notes. Over 50% of the antibiotics prescribed for administration via parenteral route were switched over to oral route after 24-48 hours or as soon as the patients could tolerate such route. This overuse of injections has also been found in an earlier study in Kathmandu valley 17. Other than the fact that the use of parenteral preparations are associated with potential risks, the dosage form is also more expensive than oral dosage forms which could have been used in many of the patients that received injectables. These indicators of irrational prescribing are potential contributors to antibiotic resistance which has been recognized in previous studies 10. Bacterial resistance to antibiotics increases morbidity and mortality as well as healthcare costs 18. It is generally preferable to keep the number of antibiotics per prescription as low as possible to minimize risk of drug interaction, development of bacterial resistance and hospital cost, and enhance patient compliance. In this study, only a few of the patients studied received as many as 4 to 5 antibiotics in a single prescription and majority received only 1 or 2 antibiotics. The average number of antibiotics prescribed was similar to what was obtained in a teaching hospital in western Nepal 19. However, the comparative evaluation of the DDDs revealed Pharmacy
that the doses prescribed for some of the patients were reasonably at variance with the internationally defined doses. While the very high doses of antibiotics prescribed for some of the patients may not necessarily have had any more advantage than the usual internationally defined daily doses, high doses are often associated with increased risk of adverse events and higher cost of hospitalization. On the other hand, the relatively lower doses than the internationally defined daily doses of some medicines like cefuroxime, ceftazidime, flucloxacillin and benzypenicillin are potential sources for the development of antimicrobial resistance. Where possible, nearly all patients would prefer to receive treatment from home to reduce cost. Since critically ill patients on antibiotics may be receiving injections in the first few days of hospitalization, a switch to oral medicines is often the case once the patients are in better positions to swallow. A high proportion of the patients studied in the different settings were either discharged on request or against medical advice most likely due to economic considerations as the patients would prefer to continue further treatment at home once they get better. Overall, the prescribing approach observed has yielded poor treatment outcomes for the patients as only 39.25% were actually confirmed cured. The problem of prescribing and poor outcomes being reported in this study may provide some clue to a recent report from a 6- month survey of medical admissions in one of the hospitals (UBTH) where very high mortality was reported 20. They are also reflections of the current relative poor training and orientation of medical doctors in the region. In the only major medical school available in the region, as many as 350 600 students are currently in a class without adequate staffing, infrastructure and other facilities. Despite the economic growth in Nigeria in the last few years, due particularly to the rising oil prices, the country remains one of the poor countries of the world with over 60% of the population living below the poverty line 21. Like in other African countries, Nigeria also remains one of the countries in high alert in relation to infectious diseases. These would have meant that the prices of essential antibiotics would be subsidized to ensure affordability by most of the population that need them. Unfortunately, this study has revealed that the patients studied, most often, paid several times more than the internationally accepted prices. While the prices of benzylpenicillin, cotromixazole and clindamycin were several times lower than the internationally accepted prices, the prices of other antibiotics remained extremely high. Fluoroquinolone group of antibiotics (ciprofloxacin and ofloxacin) were even as expensive as 12 to 14 times the internationally accepted prices. The high cost of drugs in Nigeria has often been attributed to the high cost of doing business in the country, which can be linked to various factors including high cost of transportation due to bad roads, high cost of 12
provision of electricity, import duties, security concern and many local taxes 22. Since these antibiotics have become live-savers for many patients in Nigeria, due to high resistance of many microorganisms to many other antibiotics, the prices being paid by patients for these medicines are major concern in health care delivery in Nigeria. The free market policy currently being adopted for medicines in Nigeria is counter-productive in this respect. Conclusion In this study, we have provided evidence that justifies the need for further interventional programme to improve antibiotics prescribing in Edo State in Nigeria. Irrational prescribing still exists in health facilities investigated. This include low rate of prescribing by generic names, use of antibiotics without appropriate laboratory investigations and over-use of injections, and use of doses lower or much higher than the international daily defined doses. For most antibiotics, the patients generally are paying far more than the internationally accepted prices. The need to design local approaches to deal with this problem is imperative. Treatment protocols based on wide consultation and consensus have proven effective interventions to promote rational prescribing in developed countries 18. The development and application of antibiotics policy for Nigerian hospitals is also recommended but this is unlikely to be effective without adequate training of medical students, and the health professionals. Conflict of Interest This paper is not associated with any conflict of interest. The funding of this work was from the personal resources of the authors. References 1. R. O. Laing. Rational Drug Use: An Unsolved Problem. Trop. Doc. 20: 101-103 (1990). 2. J. Quick, R. Laing, and D. Ross-Degnan. Intervention research to promote clinically effective and economically efficient use of pharmaceuticals: The International Network for Rational Use of Drugs. J. Clin. Epi. 44: 57-65 (1991). 3. P. O. Erah, G. O. Olumide, and A. O. Okhamafe. Prescribing practices in two health care facilities in Warri, Southern Nigeria: A comparative study. Trop. J. Pharm. Res. 2 (1): 173-180 (2003). 4. S. B. Soumerai, T. J. McLaughlin, and J. Avorn. Improving drug prescribing in primary care: A critical analysis of the experimental literature. Milbank. Quart. 67 (2): 268-317 (1989). 13
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