Antimicrobials sales comparison before and after the implementation of nationwide restriction policy in Saudi Arabia

doi:10.21203/rs.3.rs-2006202/v1

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Antimicrobials sales comparison before and after the implementation of nationwide restriction policy in Saudi Arabia

https://doi.org/10.21203/rs.3.rs-2006202/v1

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Background: Antimicrobials dispensing without a prescription is recognized as a pathway for the emergence of antimicrobial resistance; a serious global public health issue in need of urgent regulatory responses. In mid-2018, the Saudi Ministry of Health initiated a nationwide antimicrobial restriction policy, in which pharmacies are strictlyprohibited from dispensing antimicrobial drugs without physicians’ prescription. Therefore, the objective of this study was to determine if this restriction policy implemented by the Saudi Ministry of Health has led to decrease in antimicrobial drugs sales.

Methods: The annual retail sales information of antimicrobials was obtained from the pharmaceutical database, IQVIA-Multinational Integrated Data Analysis System (IQVIA-MIDAS®) between 2017 and 2019 to compare sales before and after the intervention. Antimicrobial drugs include the following: antibiotics; antifungals; antimycobacterials; combinations and other drugs. Nonparametric Wilcoxon Signed Rank test was used to assess changes in antimicrobials sales from pre- to post- intervention periods.

Results: Our results showed that this intervention policy has achieved significate effects in reducing total antimicrobials sales by 23.2% from 818,916,437 SAR in 2017 to 648,383,630 SAR in 2019. Wilcoxon Signed Rank test showed a statistically significant median decrease in total antimicrobials sales after the intervention with a p-value = 0.0397. Reduction in the antibiotic amoxicillin was responsible for most of the decrease in antimicrobials sales with 70% less in 2019 compared to 2017. On the contrary, continuous increase in sales of some antimicrobial drugs following the restriction policy was observed led by the antibiotic amoxicillin/clavulanic acid.

Conclusion: Our data support the implementation of antimicrobials restriction measures as an effective means of controlling excessive antimicrobials sales and dispensing without prescriptions.

IQVIA

AMR

DAwP

AWaRe

antibiotics restriction

Antimicrobial resistance (AMR) is a global health care issue that raises mortality from infectious diseases and increases healthcare costs (1, 2). According to the World Health Organization (WHO) AMR will become the leading cause of deaths worldwide by 2050 unless addressed properly (3). The dispensing of antimicrobials without a prescription (DAwP) for self-limiting conditions such as upper respiratory tract infections (URTIs) as well as urinary tract infections (UTIs) is a key driver in the emergence and spread of AMR (4). Numerous studies have confirmed a positive correlation between antimicrobials consumption and increase emergence of AMR worldwide (5–7). With the given observed decline in the rate of developing novel antimicrobials and the advent of multidrug resistance pathogens, more attention must be given prescribing policies to control antimicrobials misuse and maximize the life expectancy of a given drug. Therefore, urgent calls led by the WHO to address this issue including the development of international and country-specific intervention plans at both community and hospital settings to control antibiotics consumption rate in order to decrease AMR levels (8). Moreover, WHO established a new antibiotic classification system which is intended to facilitate proper surveillance and stewardship of antibiotic use (9). This system classifies antibiotics into three groups: Access, Watch, and Reserve (AWaRe classification). The “Access” group includes narrow spectrum antibiotics recommended as first and second option for most common infectious diseases. The “Watch” group contains broader spectrum antibiotics with higher resistance potential that represent the critical important antimicrobial drugs for human medicine. The Reserve group is considered as the last resort antibiotics for targeted use in multidrug resistant pathogens (9, 10). Various countries implemented governmental policies to enforce prohibition of DAwP and reduce spread of AMR (11–15). During previous years, prohibition of over-the-counter antimicrobial sales in private pharmacies was not enforced in Saudi Arabia, and non-prescribed use of antimicrobials was common (16). Many studies conducted across Saudi Arabia over the past years have shown that DAwP is common among pharmacists. For example, Al-Ghamdi, showed that 82.0% of 88 community pharmacies in the Eastern province of Saudi Arabia visited by simulated clients presenting cases of uncomplicated UTI were dispensed antibiotics without prescription (17). Emeka et al., found a high incidence of self- medication where colds and sore throats were the most common reasons for seeking DAwP (18). A more recent questioner showed that 70.7% of community pharmacists in Saudi Arabia reported that DAwP was common among community pharmacists before the Saudi Ministry of Health (MOH) intervention (19). For that, many educational approaches were lunched by the Saudi MOH with the focus on changing the practice of healthcare providers and increase public awareness of the importance of rationalization and optimal use of antibiotics to reduce overuse and misuse of antibiotics. Other approaches were also implemented by the Saudi MOH including several policies such as professional regulation, restricted reimbursement, and prescription requirements. In mid-2018, the Saudi MOH initiated a nationwide antibiotics restriction policy, in which pharmacies are strictly prohibited from dispensing antibiotics without physicians’ prescription. Failure to adhere to the regulations may results in high penalties for the licence owner including cancelling the license, fine of up to 100 thousand riyals, and imprisonment for up to six months. Investigating the impact of restricting sales of antimicrobials is important for informing policy decision makers about the effect of measures taken, including undesired interventions effects. Unfortunately, the effectiveness of the Saudi MOH nationwide efforts for restricting antimicrobial use has never been evaluated before. Therefore, the objective of this study was to determine if antibiotic restriction policy implemented by MOH in Saudi Arabia has led to decrease in antibiotics sales.

Study design

This is a retrospective study which involved assessing antibiotic sales one year before and after the initiation of the nationwide restriction program in Saudi Arabia in mid-2018. All antimicrobial drugs were included regardless of brand or generic name, or route of administration such as: antibiotics; antifungals; antimycobacterials; combinations and other. Antimicrobial drugs that have missing data before or after restriction policy implementation were excluded from this study.

Data collection

The main outcome of interest for this study was to determine if antibiotic restriction policy implemented by Saudi MOH in 2018 led to decrease in antibiotics sales. To do so, antimicrobials sales data during the pre-implementation phase of the sales restriction policy, 2017, and the post-implementation phase, 2019, were extracted from IQVIA-Multinational Integrated Data Analysis System (IQVIA-MIDAS®) for comparison. The year of 2018 was not included in the comparison. This is because this year is when the implementation phase took place and usually the effectiveness of such policy could take up to 3–6 months to achieve its goals. IQVIA-MIDAS® is an international commercial database company that tracks pharmaceutical sales by collecting data from of manufacturers, distributors and whole-sellers, through retail and non-retail channels. This include over-the-counter (OTC) and prescription-based antibiotics sales. In the case of Saudi Arabia, this IQVIA database comprises of 98% retail channels and 85% of public channels actual sales, and data coverage is projected to cover 100% of all sales information in the near future (20 Antibiotics were categorized according to the WHO (AWaRe) classification (Access, Watch, Reserve), or unclassified for antifungals and antimycobacterials (21). The full list of antimicrobial drugs and classes are included in in Table 1.

Statistical analysis

The normality of the differences for the antimicrobials sales data was tested using Kolmogorov–Smirnov normality test (22). Since the antimicrobial sales data were not normally distributed, but rather skewed towards specific drugs, nonparametric Wilcoxon Signed Rank test for paired samples was used. Here, we applied this test to the overall antimicrobial sales to compare intervention outcomes between pre-intervention sales period (2017) and post- intervention sales period (2019). The statistical significance was set at p < 0.05. Analysis was conducted with R Version (3.6.3).

In this study, a total of 38 antimicrobials were extracted from IQVIA database including 25 antibiotics belongs to different classes (Penicillins, Beta-lactam/beta-lactamase-inhibitor, Macrolides, First, Second, Third Generation Cephalosporin, Quinolones/Fluoroquinolones, Tetracycline, and oxazolidinones), 5 antifungals, 3 Antimycobacterials, 4 combinations, and one was classified as “other” (Table 1). On average, the total sales of antimicrobials decreased by 23.2% from 818,916,437 SAR in 2017 to 648,383,630 SAR in 2019. Nonparametric Wilcoxon Signed Rank test was applied to the overall antimicrobials sales before and after restriction. This test showed that there was a statistically significant median decrease in antimicrobials sales after the intervention in 2019 compared to sales before the intervention in 2017 with a p-value = 0.0397 (Table 2). Twenty four out of 38 (63.2%) of antimicrobials showed decline in sales after the restriction, where sales were 420,123,138 SAR before restriction and decreased to 186,143,367 SAR after restriction. Out of theses 24 antimicrobials 12 were classified as “Watch” according to WHO AWaRe classification, 7 were classified as “Access”, one as “Reserve”, and one unclassified. On the contrary, 14 out of the 38 of the antimicrobials (36.8%) showed increase in sales from 398,793,299 SAR in 2017 to 462,240,263 SAR in 2019. Out of these 14 antimicrobials, 8 were classified as “watch”, 2 as “Access”, one as “Reserved”, and 3 “unclassified”. The antibiotics penicillin and combinations of penicillin with ß-lactamase inhibitors accounted for more than 50 % of the total procurement sales for all drugs, yet the restriction was effective only in reducing penicillin (Amoxicillin) sales by 70% form 208,562,130 SAR before intervention in 2017 to 61,968,664 SAR after intervention in 2019. (Table 1 and Figure 1). Unlike penicillin, the intervention effects were limited for the sales of combinations of penicillin with ß-lactamase inhibitors (Amoxicillin-Clavulanic Acid) with an increase in sales of 17,673,993 SAR (6.5%) in 2019 compared to 2017. All antimicrobial sales information during pre- and post- intervention are listed in Table 1.

Table 2: Wilcoxon signed rank test to compare differences in antimicrobials sales from 2017 (pre- intervention period) to 2019 (post- intervention period). The statistical significance was set at p < 0.05.

Median

IQR

Z- value

P- value

Pre-intervention sales (SAR)

3456845

17337604

-864730.5

0.0396

Post- intervention sales (SAR)

2389661

11374585

The main objective of this study was to investigate the impact of the MOH regulation on antimicrobial sales in Saudi Arabia by comparing sales before and after the implementation restrictive measures. Our data demonstrated that a significant reduction of total sales of antimicrobials was observed in 2019 compared to sales in 2017. This antibiotic sales decrease was following the restriction policy implemented in 2018, suggesting that this decrease in sales might be associated with successful intervention. This comes in agreement with previous studies that showed a direct reduction in antimicrobial sales after policies intervention in many countries around the world (23–28). The reduction in sales was mainly led by penicillin (Amoxicillin) with 70% less in 2019 compared to 2017, indicating that the inappropriate use of penicillin may have diminished after the restrictions were enforced. However, follow up investigations in subsequent years are required to confirm if this decline in sales is rather true effect of the restriction than an isolated incident. Our results also showed continuous increase in sales for some antimicrobials after intervention (Table 1). Unfortunately, most of these antimicrobials are classified as “Watch” according to WHO classification system. This was not expected given the restrict policy implemented by MOH and governmental potential fines, indicating a relatively inadequate prescribing practice. Of note, the sales of broad-spectrum antibiotics (amoxicillin/clavulanate) increased by 10% in 2019 compared to 2017, and this one drug was responsible for the general increase in total antibiotic sales as it holds the highest sales. The antibiotic amoxicillin/clavulanate belongs to broad spectrum penicillin with ß-lactamase inhibitors that is recommended for treatment of common infectious conditions (such as community acquired pneumonia and urinary tract infections) and is considered as “Access” antibiotic (21). One global study showed that amoxicillin/clavulanate was the most sold antibiotic in 75 countries and accounted for about 50% of sales (13(.

Our study shows that some broad-spectrum antibiotics presented continuous increase in sales after the intervention; Azithromycin, Clarithromycin, Cefalexin, Cefdinir, Levofloxacin, and Moxifloxacin. These are medication used to treat bacterial infections in many parts of the human body and all categorized as “Watch” antibiotics (21). The observed continuous increase in sales of broad-spectrum antibiotics in our data comes in agreement with previous findings that showed that the percentage of broad-spectrum antibiotic prescriptions did not achieve significant decline after intervention (26). Similarly, a shift from the use of narrow-spectrum antibiotics towards broad-spectrum antibiotics after intervention was observed in European countries (29). In China, prescribing of broad-spectrum antibiotics was still prevalent even after the implementation of the 2011 national antimicrobial stewardship campaign (30). Unfortunately, the misuse of broad-spectrum antibiotics has contributed tremendously to the development of multidrug-resistant pathogens, unlike targeted use of narrow-spectrum antibiotics (31). This continues increase in broad spectrum antibiotics sales even after restriction measures have taken could be because this class of antibiotics are usually inappropriately prescribed even in situations where narrow-spectrum counterparts maybe more suitable. This is because physicians generally tend to broaden empiric antibacterial therapy before the microbiological test results were known, which may elevate the difficulty of reducing broad-spectrum antibiotic sales and use. Therefore, primary care physicians and their patients should be potential targets for intervention guidelines into daily clinical practice especially in the private sector. Other reasons could be because some of narrow-spectrum drugs are relatively new and got introduced to the market during the intervention period or due to the convenience of once daily dosing use or probably the low cost. However, further research is needed to explore other factors such as the economic and population growth factors that could be contributing to the changes in antimicrobial sales in this country.

To the best of our knowledge, the present study is the first study to provide Saudi policy makers with validated outcomes on specific governmental intervention addressing previous uncontrolled antimicrobials sales. However, several limitations in this study need to be addressed. First, IQVIA database do not distinguish sales of prescription from non-prescription antimicrobials, therefore, drug sales do not accurately reflect consumption patterns in Saudi Arabia. Second, IQVIA database include all antimicrobial sales from both private and public sectors. Therefore, changes in sales after restriction could have a greater impact on the private sector given that in the public sector a prescription is needed to get medicines even before the regulation. Third, the observed reduction in total antimicrobial sales in our study could be attributed to other factors besides the restriction policy such as: socioeconomic factors, government inspections, prescribing practices, and seasonality effects. Finally, we acknowledge that our results may not reflect the full picture of the restriction policy impact on antimicrobial use in Saudi Arabia, yet it gives an indication of the governmental intervention effect. Despite limitations, this study may be considered as a baseline for further studies to evaluate the effectiveness of MOH interventions. Since the MOH implementations were recently applied in Saudi Arabia, further studies must be conducted to evaluate whether these policies have changed the profile of antibiotic use and antimicrobial resistance rate.

This study showed that after implementing new measures to restrict antimicrobial drugs sales in Saudi Arabia, the overall increasing sales of antibiotics was reduced after the second year of implementation. Our data support the use of an antimicrobial restriction programs as an effective means of controlling excessive antimicrobial sales and dispensing of antimicrobials without a prescription.

IQVIA-MIDAS: IQVIA-Multinational Integrated Data Analysis System

AMR: Antimicrobial resistance

WHO: World Health Organization

DAwP: Dispensing of antimicrobials without a prescription

URTIs: Upper respiratory tract infections

UTIs: Urinary tract infections

AWaRe: Access, Watch, and Reserve

MOH: Ministry of Health

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The data set that support the findings of this study are available from IQVIA™ Saudi Arabia.

Competing interests

The authors declare that they have no competing interests.

Funding

None.

Authors' Contributions

SMA* and KOA participated in the conception and design of the study. MMA was involved in the data collection. KOA and AA were involved in data analysis. KOA and SMA* were involved in preparing the manuscript. KOA, SMA*, AA, SMA were involved in reviewing and editing the manuscript. SMA was involved in supervising. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Sulaiman M. Alajel(SMA*).

Acknowledgements

IQVIA provide all support needed for the retrieval of the sale data that were used in this project. The findings and conclusions of this report are those of the authors and do not necessarily represent the official views or policies of the SFDA.

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Antimicrobials sales comparison before and after the implementation of nationwide restriction policy in Saudi Arabia

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Abstract

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Background

Methods

Study design

Data collection

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Table

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